From b05ea25ac03fd77623e305724ef03d3ca08fee76 Mon Sep 17 00:00:00 2001 From: Aditya Nath Date: Fri, 14 Feb 2025 15:48:01 -0800 Subject: [PATCH 1/2] Prelim fixes for mc2-center-dcc scripts relating to upload_workflow.sh --- annotations/input/jan25_filepaths.csv | 5 +++ annotations/input/jan25_pubs.csv | 31 ++++++++++++++ annotations/input/nov_datasets.csv | 18 +++++++++ annotations/input/nov_filepaths.csv | 45 +++++++++++++++++++++ annotations/input/nov_pubs.csv | 48 ++++++++++++++++++++++ annotations/oct_filepaths.csv | 50 +++++++++++++++++++++++ annotations/oct_manifest.csv | 58 +++++++++++++++++++++++++++ annotations/processing-splits.py | 8 +++- annotations/split_manifest_grants.py | 0 annotations/upload-workflow.sh | 39 +++++++++++------- 10 files changed, 286 insertions(+), 16 deletions(-) create mode 100644 annotations/input/jan25_filepaths.csv create mode 100644 annotations/input/jan25_pubs.csv create mode 100644 annotations/input/nov_datasets.csv create mode 100644 annotations/input/nov_filepaths.csv create mode 100644 annotations/input/nov_pubs.csv create mode 100644 annotations/oct_filepaths.csv create mode 100755 annotations/oct_manifest.csv mode change 100644 => 100755 annotations/split_manifest_grants.py mode change 100644 => 100755 annotations/upload-workflow.sh diff --git a/annotations/input/jan25_filepaths.csv b/annotations/input/jan25_filepaths.csv new file mode 100644 index 00000000..7daba32d --- /dev/null +++ b/annotations/input/jan25_filepaths.csv @@ -0,0 +1,5 @@ +File Paths,folderIdPublication +/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA245313_publication.csv,syn32698418 +/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA225088_publication.csv,syn32698012 +/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA282451_publication.csv,syn53212972 +/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA232216_publication.csv,syn32698110 diff --git a/annotations/input/jan25_pubs.csv b/annotations/input/jan25_pubs.csv new file mode 100644 index 00000000..ca09a3bd --- /dev/null +++ b/annotations/input/jan25_pubs.csv @@ -0,0 +1,31 @@ +Component,Publication Grant Number,Publication Consortium Name,Publication Theme Name,Publication Doi,Publication Journal,Pubmed Id,Pubmed Url,Publication Title,Publication Year,Publication Keywords,Publication Authors,Publication Abstract,Publication Assay,Publication Tumor Type,Publication Tissue,Publication Dataset Alias,Publication Accessibility +PublicationView,CA274502,CSBC,"Computational Resource, Heterogeneity",https://doi.org/10.1016/j.devcel.2024.11.021,Dev Cell,39706188,https://pubmed.ncbi.nlm.nih.gov/39706188,Global versus local matrix remodeling drives rotational versus invasive collective migration of epithelial cells,2024,"Matrix Metalloproteinase, adhesion, Mt1-mmp, Matrix Remodeling, Collective Migration, Adherens Junctions, Invasive Migration, Itgβ1, Rotational Migration","Sural K Ranamukhaarachchi, Alyssa Walker, Man-Ho Tang, William D Leineweber, Sophia Lam, Wouter-Jan Rappel, Stephanie I Fraley","The coordinated movement of cell collectives is essential for normal epithelial tissue development, maintenance, and cancer progression. Here, we report on a minimal 3D extracellular matrix (ECM) system wherein both invasive collective migration (ICM) and rotational collective migration (RCM) arise spontaneously from individually seeded epithelial cells of mammary and hepatic origin, regardless of whether they express adherens junctions, and lead to ductal-like and acinar-like structures, respectively. Quantitative microscopy and cellular Potts modeling reveal that initial differences in cell protrusion dynamics and matrix-remodeling localization generate RCM and ICM behavior in confining 3D ECM. Matrix-remodeling activity by matrix metalloproteinases (MMPs) is localized to the base of protrusions in cells that initiate ICM, whereas RCM does not require MMPs and is associated with ITGβ1-mediated remodeling localized globally around the cell body. Further analysis in vitro and in vivo supports the concept that distinct matrix-remodeling strategies encode collective migration behaviors and tissue structure.","Western Blotting, Fluorescence Imaging, Immunohistochemistry Staining Method",Pan-cancer,Not Applicable,,Open Access +PublicationView,CA253472,CSBC,"Tumor-Immune, Drug Resistance/Sensitivity",https://doi.org/10.1186/s13073-024-01393-6,Genome Med,39468667,https://pubmed.ncbi.nlm.nih.gov/39468667,Developmental-status-aware transcriptional decomposition establishes a cell state panorama of human cancers,2024,"Cell differentiation, organogenesis, Gene Expression, Stemness, Tcga, Pan-cancer, Scrna-seq, Prognostic And Predictive Biomarkers, Oncofetal Reprogramming, Transcriptional Decomposition","Yikai Luo, Han Liang","Background: Cancer cells evolve under unique functional adaptations that unlock transcriptional programs embedded in adult stem and progenitor-like cells for progression, metastasis, and therapeutic resistance. However, it remains challenging to quantify the stemness-aware cell state of a tumor based on its gene expression profile. Methods: We develop a developmental-status-aware transcriptional decomposition strategy using single-cell RNA-sequencing-derived tissue-specific fetal and adult cell signatures as anchors. We apply our method to various biological contexts, including developing human organs, adult human tissues, experimentally induced differentiation cultures, and bulk human tumors, to benchmark its performance and to reveal novel biology of entangled developmental signaling in oncogenic processes. Results: Our strategy successfully captures complex dynamics in developmental tissue bulks, reveals remarkable cellular heterogeneity in adult tissues, and resolves the ambiguity of cell identities in in vitro transformations. Applying it to large patient cohorts of bulk RNA-seq, we identify clinically relevant cell-of-origin patterns and observe that decomposed fetal cell signals significantly increase in tumors versus normal tissues and metastases versus primary tumors. Across cancer types, the inferred fetal-state strength outperforms published stemness indices in predicting patient survival and confers substantially improved predictive power for therapeutic responses. Conclusions: Our study not only provides a general approach to quantifying developmental-status-aware cell states of bulk samples but also constructs an information-rich, biologically interpretable, cell-state panorama of human cancers, enabling diverse translational applications.","RNA Sequencing, Mathematical Modeling",Pan-cancer,Not Applicable,,Open Access +PublicationView,CA261701,MetNet,"Tumor-Immune, Metastasis, Microenvironment",https://doi.org/10.1038/s41586-024-07767-5,Nature,39112700,https://pubmed.ncbi.nlm.nih.gov/39112700,Neuronal substance P drives metastasis through an extracellular RNA-TLR7 axis,2024,,"Veena Padmanaban, Isabel Keller, Ethan S Seltzer, Benjamin N Ostendorf, Zachary Kerner, Sohail F Tavazoie","Tumour innervation is associated with worse patient outcomes in multiple cancers1,2, which suggests that it may regulate metastasis. Here we observed that highly metastatic mouse mammary tumours acquired more innervation than did less-metastatic tumours. This enhanced innervation was driven by expression of the axon-guidance molecule SLIT2 in tumour vasculature. Breast cancer cells induced spontaneous calcium activity in sensory neurons and elicited release of the neuropeptide substance P (SP). Using three-dimensional co-cultures and in vivo models, we found that neuronal SP promoted breast tumour growth, invasion and metastasis. Moreover, patient tumours with elevated SP exhibited enhanced lymph node metastatic spread. SP acted on tumoral tachykinin receptors (TACR1) to drive death of a small population of TACR1high cancer cells. Single-stranded RNAs (ssRNAs) released from dying cells acted on neighbouring tumoural Toll-like receptor 7 (TLR7) to non-canonically activate a prometastatic gene expression program. This SP- and ssRNA-induced Tlr7 gene expression signature was associated with reduced breast cancer survival outcomes. Therapeutic targeting of this neuro-cancer axis with the TACR1 antagonist aprepitant, an approved anti-nausea drug, suppressed breast cancer growth and metastasis in multiple models. Our findings reveal that tumour-induced hyperactivation of sensory neurons regulates multiple aspects of metastatic progression in breast cancer through a therapeutically targetable neuropeptide/extracellular ssRNA sensing axis.","Murine Model, Viral Transduction, siRNA, Western Blotting, Fluorescence Imaging, qPCR, Flow Cytometry, RNA Sequencing",Breast Carcinoma,Breast,"SRX24613796, GSE267958, SRP508791, SRX24613794, SRX24613789, SRX24613792, SRX24613791, SRX24613795, SRX24613790, SRX24613793",Open Access +PublicationView,CA214297,PS-ON,"Metastasis, Microenvironment",https://doi.org/10.1038/s41467-024-55140-x,Nat Commun,39746954,https://pubmed.ncbi.nlm.nih.gov/39746954,Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product,2025,,"Avanish Mishra, Shih-Bo Huang, Taronish Dubash, Risa Burr, Jon F Edd, Ben S Wittner, Quinn E Cunneely, Victor R Putaturo, Akansha Deshpande, Ezgi Antmen, Kaustav A Gopinathan, Keisuke Otani, Yoshiyuki Miyazawa, Ji Eun Kwak, Sara Y Guay, Justin Kelly, John Walsh, Linda T Nieman, Isabella Galler, PuiYee Chan, Michael S Lawrence, Ryan J Sullivan, Aditya Bardia, Douglas S Micalizzi, Lecia V Sequist, Richard J Lee, Joseph W Franses, David T Ting, Patricia A R Brunker, Shyamala Maheswaran, David T Miyamoto, Daniel A Haber, Mehmet Toner","Circulating Tumor Cells (CTCs) in blood encompass DNA, RNA, and protein biomarkers, but clinical utility is limited by their rarity. To enable tumor epitope-agnostic interrogation of large blood volumes, we developed a high-throughput microfluidic device, depleting hematopoietic cells through high-flow channels and force-amplifying magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.83 liters from seven patients with metastatic cancer. High CTC yields (mean 10,057 CTCs per patient; range 100 to 58,125) reveal considerable intra-patient heterogeneity. CTC size varies within patients, with 67% overlapping in diameter with WBCs. Paired single-cell DNA and RNA sequencing identifies subclonal patterns of aneuploidy and distinct signaling pathways within CTCs. In prostate cancers, a subpopulation of small aneuploid cells lacking epithelial markers is enriched for neuroendocrine signatures. Pooling of CNV-confirmed CTCs enables whole exome sequencing with high mutant allele fractions. High-throughput CTC enrichment thus enables cell-based liquid biopsy for comprehensive monitoring of cancer.","RNA Sequencing, Droplet Digital PCR",Pan-Cancer,Not Applicable,,Open Access +PublicationView,CA210152,PS-ON,"Metastasis, Microenvironment",https://doi.org/10.1016/j.neo.2024.101036,Neoplasia,39173508,https://pubmed.ncbi.nlm.nih.gov/39173508,Characterization of circulating tumor cells in patients with metastatic bladder cancer utilizing functionalized microfluidics,2024,"EGFR, Differential gene expression, Bladder cancer, Her2, Cd31, Circulating Tumor Cells, Adam15, Targeted Transcriptome Sequencing, Graphene Oxide Microfluidic Chip","Zeqi Niu, Molly Kozminsky, Kathleen C Day, Luke J Broses, Marian L Henderson, Christopher Patsalis, Rebecca Tagett, Zhaoping Qin, Sarah Blumberg, Zachery R Reichert, Sofia D Merajver, Aaron M Udager, Phillip L Palmbos, Sunitha Nagrath, Mark L Day","Assessing the molecular profiles of bladder cancer (BC) from patients with locally advanced or metastatic disease provides valuable insights, such as identification of invasive markers, to guide personalized treatment. Currently, most molecular profiling of BC is based on highly invasive biopsy or transurethral tumor resection. Liquid biopsy takes advantage of less-invasive procedures to longitudinally profile disease. Circulating tumor cells (CTCs) isolated from blood are one of the key analytes of liquid biopsy. In this study, we developed a protein and mRNA co-analysis workflow for BC CTCs utilizing the graphene oxide (GO) microfluidic chip. The GO chip was conjugated with antibodies against both EpCAM and EGFR to isolate CTCs from 1 mL of blood drawn from BC patients. Following CTC capture, protein and mRNA were analyzed using immunofluorescent staining and ion-torrent-based whole transcriptome sequencing, respectively. Elevated CTC counts were significantly associated with patient disease status at the time of blood draw. We found a count greater than 2.5 CTCs per mL was associated with shorter overall survival. The invasive markers EGFR, HER2, CD31, and ADAM15 were detected in CTC subpopulations. Whole transcriptome sequencing showed distinct RNA expression profiles from patients with or without tumor burden at the time of blood draw. In patients with advanced metastatic disease, we found significant upregulation of metastasis-related and chemotherapy-resistant genes. This methodology demonstrates the capability of GO chip-based assays to identify tumor-related RNA signatures, highlighting the prognostic potential of CTCs in metastatic BC patients.","Fluorescence Imaging, Mathematical Modeling",Bladder Carcinoma,Bladder,,Open Access +PublicationView,CA268084,CCBIR,"Platform Development, Epigenetics, Computational Model Development",https://doi.org/10.3389/fnmol.2024.1484964,Front Mol Neurosci,39703720,https://pubmed.ncbi.nlm.nih.gov/39703720,Transcorneal electrical stimulation restores DNA methylation changes in retinal degeneration,2024,"Retina, DNA methylation, Electrical stimulation, epigenomics, Retinal degeneration","Ben Yi Tew, Gerald C Gooden, Pei-An Lo, Dimitrios Pollalis, Brandon Ebright, Alex J Kalfa, Alejandra Gonzalez-Calle, Biju Thomas, David N Buckley, Thomas Simon, Zeyi Yang, Ege Iseri, Cody L Dunton, Vadim Backman, Stan Louie, Gianluca Lazzi, Mark S Humayun, Bodour Salhia","Background: Retinal degeneration is a major cause of irreversible blindness. Stimulation with controlled low-level electrical fields, such as transcorneal electrical stimulation (TES), has recently been postulated as a therapeutic strategy. With promising results, there is a need for detailed molecular characterization of the therapeutic effects of TES. Methods: Controlled, non-invasive TES was delivered using a custom contact lens electrode to the retinas of Royal College of Surgeons (RCS) rats, a model of retinal degeneration. DNA methylation in the retina, brain and cell-free DNA in plasma was assessed by reduced representation bisulfite sequencing (RRBS) and gene expression by RNA sequencing. Results: TES induced DNA methylation and gene expression changes implicated in neuroprotection in the retina of RCS rats. We devised an epigenomic-based retinal health score, derived from DNA methylation changes observed with disease progression in RCS rats, and showed that TES improved the epigenomic health of the retina. TES also induced DNA methylation changes in the superior colliculus: the brain which is involved in integrating visual signaling. Lastly, we demonstrated that TES-induced retinal DNA methylation changes were detectable in cell-free DNA derived from plasma. Conclusion: TES induced DNA methylation changes with therapeutic effects, which can be measured in circulation. Based on these changes, we were able to devise a liquid biopsy biomarker for retinal health. These findings shed light on the therapeutic potential and molecular underpinnings of TES, and provide a foundation for the further development of TES to improve the retinal health of patients with degenerative eye diseases.","Murine Model, Bisulfite Sequencing, RNA Sequencing",Retinoblastoma,Eye,,Open Access +PublicationView,CA217617,PDMC,"Drug Resistance/Sensitivity, Experimental Model Development",https://doi.org/10.1016/j.xpro.2023.102402,STAR Protoc,37402170,https://pubmed.ncbi.nlm.nih.gov/37402170,Breast cancer PDxO cultures for drug discovery and functional precision oncology,2023,"Cancer, Cell culture, Organoids, Model Organisms, Cell-based Assays","Sandra D Scherer, Ling Zhao, Andrew J Butterfield, Chieh-Hsiang Yang, Emilio Cortes-Sanchez, Katrin P Guillen, Bryan E Welm, Alana L Welm","Patient-derived xenografts (PDXs) have clinical value but are time-, cost-, and labor-intensive and thus ill-suited for large-scale experiments. Here, we present a protocol to convert PDX tumors into PDxOs for long-term cultures amenable to moderate-throughput drug screens, including in-depth PDxO validation. We describe steps for PDxO preparation and mouse cell removal. We then detail PDxO validation and characterization and drug response assay. Our PDxO drug screening platform can predict therapy response in vivo and inform functional precision oncology for patients. For complete details on the use and execution of this protocol, please refer to Guillen et al.1.",Patient Derived Xenograft,Pan-cancer,Not Applicable,,Open Access +PublicationView,CA274499,CSBC,"Oncogenic Stress, Metabolism",https://doi.org/10.1186/s13058-024-01931-5,Breast Cancer Res,39741344,https://pubmed.ncbi.nlm.nih.gov/39741344,Patient-derived response estimates from zero-passage organoids of luminal breast cancer,2024,"Matrigel, Tamoxifen, systems biology, sulforaphane, Nqo1, Luminal, Organoid, Tp73","Róża K Przanowska, Najwa Labban, Piotr Przanowski, Russell B Hawes, Kristen A Atkins, Shayna L Showalter, Kevin A Janes","Background: Primary luminal breast cancer cells lose their identity rapidly in standard tissue culture, which is problematic for testing hormone interventions and molecular pathways specific to the luminal subtype. Breast cancer organoids are thought to retain tumor characteristics better, but long-term viability of luminal-subtype cases is a persistent challenge. Our goal was to adapt short-term organoids of luminal breast cancer for parallel testing of genetic and pharmacologic perturbations. Methods: We freshly isolated patient-derived cells from luminal tumor scrapes, miniaturized the organoid format into 5 µl replicates for increased throughput, and set an endpoint of 14 days to minimize drift. Therapeutic hormone targeting was mimicked in these ""zero-passage"" organoids by withdrawing β-estradiol and adding 4-hydroxytamoxifen. We also examined sulforaphane as an electrophilic stress and commercial nutraceutical with reported anti-cancer properties. Downstream mechanisms were tested genetically by lentiviral transduction of two complementary sgRNAs and Cas9 stabilization for the first week of organoid culture. Transcriptional changes were measured by RT-qPCR or RNA sequencing (RNA-seq), and organoid phenotypes were quantified by serial brightfield imaging, digital image segmentation, and regression modeling of volumetric growth rates. Results: We achieved > 50% success in initiating luminal breast cancer organoids from tumor scrapes and maintaining them to the 14-day zero-passage endpoint. Success was mostly independent of clinical parameters, supporting general applicability of the approach. Abundance of ESR1 and PGR in zero-passage organoids consistently remained within the range of patient variability at the endpoint. However, responsiveness to hormone withdrawal and blockade was highly variable among luminal breast cancer cases tested. Combining sulforaphane with knockout of NQO1 (a phase II antioxidant response gene and downstream effector of sulforaphane) also yielded a breadth of organoid growth phenotypes, including growth inhibition with sulforaphane, growth promotion with NQO1 knockout, and growth antagonism when combined. Conclusions: Zero-passage organoids are a rapid and scalable way to interrogate properties of luminal breast cancer cells from patient-derived material. This includes testing drug mechanisms of action in different clinical cohorts. A future goal is to relate inter-patient variability of zero-passage organoids to long-term outcomes.","RNA Sequencing, RT-qPCR, Viral Transduction, Western Blotting",Breast Carcinoma,Breast,,Open Access +PublicationView,CA268069,CCBIR,"Platform Development, Tumor-Immune, Immunotherapy, Microenvironment",https://doi.org/10.3390/ijms25094706,Int J Mol Sci,38731924,https://pubmed.ncbi.nlm.nih.gov/38731924,Implementation of FRET Spectrometry Using Temporally Resolved Fluorescence: A Feasibility Study,2024,"Protein quaternary structure, Fluorescence Lifetime Imaging Microscopy (Flim), Protein–protein Interactions, Förster Resonance Energy Transfer (Fret), Fret Spectrometry, Spectrally Resolved Fluorescence, Temporally Resolved Fluorescence","Justin Trujillo, Aliyah S Khan, Dhruba P Adhikari, Michael R Stoneman, Jenu V Chacko, Kevin W Eliceiri, Valerica Raicu","Förster resonance energy transfer (FRET) spectrometry is a method for determining the quaternary structure of protein oligomers from distributions of FRET efficiencies that are drawn from pixels of fluorescence images of cells expressing the proteins of interest. FRET spectrometry protocols currently rely on obtaining spectrally resolved fluorescence data from intensity-based experiments. Another imaging method, fluorescence lifetime imaging microscopy (FLIM), is a widely used alternative to compute FRET efficiencies for each pixel in an image from the reduction of the fluorescence lifetime of the donors caused by FRET. In FLIM studies of oligomers with different proportions of donors and acceptors, the donor lifetimes may be obtained by fitting the temporally resolved fluorescence decay data with a predetermined number of exponential decay curves. However, this requires knowledge of the number and the relative arrangement of the fluorescent proteins in the sample, which is precisely the goal of FRET spectrometry, thus creating a conundrum that has prevented users of FLIM instruments from performing FRET spectrometry. Here, we describe an attempt to implement FRET spectrometry on temporally resolved fluorescence microscopes by using an integration-based method of computing the FRET efficiency from fluorescence decay curves. This method, which we dubbed time-integrated FRET (or tiFRET), was tested on oligomeric fluorescent protein constructs expressed in the cytoplasm of living cells. The present results show that tiFRET is a promising way of implementing FRET spectrometry and suggest potential instrument adjustments for increasing accuracy and resolution in this kind of study.",Forster Resonance Energy Transfer,Pan-cancer,Not Applicable,,Open Access +PublicationView,CA248890,TEC,"Platform Development, Tumor Progression",https://doi.org/10.1039/d4lc00771a,Lab Chip,39659219,https://pubmed.ncbi.nlm.nih.gov/39659219,Retinal organoid chip: engineering a physiomimetic oxygen gradient for optimizing long term culture of human retinal organoids,2024,,"Emma Drabbe, Daniel Pelaez, Ashutosh Agarwal","An oxygen gradient across the retina plays a crucial role in its development and function. The inner retina resides in a hypoxic environment (2% O2) adjacent to the vitreous cavity. Oxygenation levels rapidly increase towards the outer retina (18% O2) at the choroid. In addition to retinal stratification, oxygen levels are critical for the health of retinal ganglion cells (RGCs), which relay visual information from the retina to the brain. Human stem cell derived retinal organoids are being engineered to mimic the structure and function of human retina for applications such as disease modeling, development of therapeutics, and cell replacement therapies. However, rapid degeneration of the retinal ganglion cell layers are a common limitation of human retinal organoid platforms. We report the design of a novel retinal organoid chip (ROC) that maintains a physiologically relevant oxygen gradient and allows the maturation of inner and outer retinal cell phenotypes for human retinal organoids. Our PDMS-free ROC holds 55 individual retinal organoids that were manually seeded, cultured for extended periods (over 150 days), imaged in situ, and retrieved. ROC was designed from first principles of liquid and gas mass transport, and fabricated from biologically- and chemically inert materials using rapid prototyping techniques such as micromachining, laser cutting, 3D printing and bonding. After computational and experimental validation of oxygen gradients, human induced pluripotent stem cell derived retinal organoids were transferred into the ROC, differentiated, cultured and imaged within the chip. ROCs that maintained active perfusion and stable oxygen gradients were successful in inducing higher viability of RGCs within retinal organoids than static controls, or ROC without oxygen gradients. Our physiologically relevant and higher-throughput retinal organoid culture system is well suited for applications in studying developmental perturbations to primate retinogenesis, including those driven by inherited traits, fetal environmental exposure to toxic agents, or acquired by genetic mutations, such as retinoblastoma.","Fluorescence Imaging, Organoid",Retinoblastoma,Eye,,Open Access +PublicationView,CA274502,CSBC,"Computational Resource, Heterogeneity",https://doi.org/10.1016/j.cell.2024.10.038,Cell,39547210,https://pubmed.ncbi.nlm.nih.gov/39547210,Discovery and significance of protein-protein interactions in health and disease,2024,,"Jack F Greenblatt, Bruce M Alberts, Nevan J Krogan","The identification of individual protein-protein interactions (PPIs) began more than 40 years ago, using protein affinity chromatography and antibody co-immunoprecipitation. As new technologies emerged, analysis of PPIs increased to a genome-wide scale with the introduction of intracellular tagging methods, affinity purification (AP) followed by mass spectrometry (MS), and co-fractionation MS (CF-MS). Now, combining the resulting catalogs of interactions with complementary methods, including crosslinking MS (XL-MS) and cryogenic electron microscopy (cryo-EM), helps distinguish direct interactions from indirect ones within the same or between different protein complexes. These powerful approaches and the promise of artificial intelligence applications like AlphaFold herald a future where PPIs and protein complexes, including energy-driven protein machines, will be understood in exquisite detail, unlocking new insights in the contexts of both basic biology and disease.",,Pan-cancer,Not Applicable,,Open Access +PublicationView,CA274502,CSBC,"Computational Resource, Heterogeneity",https://doi.org/10.1039/d4sm00971a,Soft Matter,39552222,https://pubmed.ncbi.nlm.nih.gov/39552222,Modeling collagen fibril degradation as a function of matrix microarchitecture,2024,,"Bhanjan Debnath, Badri Narayanan Narasimhan, Stephanie I Fraley, Padmini Rangamani","Collagenolytic degradation is a process fundamental to tissue remodeling. The microarchitecture of collagen fibril networks changes during development, aging, and disease. Such changes to microarchitecture are often accompanied by changes in matrix degradability. In a matrix, the pore size and fibril characteristics such as length, diameter, number, orientation, and curvature are the major variables that define the microarchitecture. In vitro, collagen matrices of the same concentration but different microarchitectures also vary in degradation rate. How do different microarchitectures affect matrix degradation? To answer this question, we developed a computational model of collagen degradation. We first developed a lattice model that describes collagen degradation at the scale of a single fibril. We then extended this model to investigate the role of microarchitecture using Brownian dynamics simulation of enzymes in a multi-fibril three dimensional matrix to predict its degradability. Our simulations predict that the distribution of enzymes around the fibrils is non-uniform and depends on the microarchitecture of the matrix. This non-uniformity in enzyme distribution can lead to different extents of degradability for matrices of different microarchitectures. Our simulations predict that for the same enzyme concentration and collagen concentration, a matrix with thicker fibrils degrades more than that with thinner fibrils. Our model predictions were tested using in vitro experiments with synthetic collagen gels of different microarchitectures. Experiments showed that indeed degradation of collagen depends on the matrix architecture and fibril thickness. In summary, our study shows that the microarchitecture of the collagen matrix is an important determinant of its degradability.",,,,,Restricted Access +PublicationView,CA243072,CSBC,Drug Resistance/Sensitivity,https://doi.org/10.1038/s41375-024-02493-3,Leukemia,39681640,https://pubmed.ncbi.nlm.nih.gov/39681640,Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia,2024,,"Tommaso Balestra, Lisa M Niswander, Asen Bagashev, Joseph P Loftus, Savannah L Ross, Robert K Chen, Samantha M McClellan, Jacob J Junco, Diego A Bárcenas López, Karen R Rabin, Terry J Fry, Sarah K Tasian","CRLF2 rearrangements occur in >50% of Ph-like and Down syndrome (DS)-associated B-acute lymphoblastic leukemia (ALL) and induce constitutive kinase signaling targetable by the JAK1/2 inhibitor ruxolitinib under current clinical investigation. While chimeric antigen receptor T cell (CART) immunotherapies have achieved remarkable remission rates in children with relapsed/refractory B-ALL, ~50% of CD19CART-treated patients relapse again, many with CD19 antigen loss. We previously reported preclinical activity of thymic stromal lymphopoietin receptor-targeted cellular immunotherapy (TSLPRCART) against CRLF2-overexpressing ALL as an alternative approach. In this study, we posited that combinatorial TSLPRCART and ruxolitinib would have superior activity and first validated potent TSLPRCART-induced inhibition of leukemia proliferation in vitro in CRLF2-rearranged ALL cell lines and in vivo in Ph-like and DS-ALL patient-derived xenograft (PDX) models. However, simultaneous TSLPRCART/ruxolitinib or CD19CART/ruxolitinib treatment during initial CART expansion diminished T cell proliferation, blunted cytokine production, and/or facilitated leukemia relapse, which was abrogated by time-sequenced/delayed ruxolitinib co-exposure. Importantly, ruxolitinib co-administration prevented fatal TSLPRCART cytokine-associated toxicity in ALL PDX mice. Upon ruxolitinib withdrawal, TSLPRCART functionality recovered in vivo with clearance of subsequent ALL rechallenge. These translational studies demonstrate an effective two-pronged therapeutic strategy that mitigates acute CART-induced hyperinflammation and provides potential anti-leukemia 'maintenance' relapse prevention for CRLF2-rearranged Ph-like and DS-ALL.","Flow Cytometry, Xenograft",Leukemia,Blood,,Open Access +PublicationView,CA261719,MetNet,"Tumor-Immune, Metastasis, Microenvironment, Computational Model Development",https://doi.org/10.1126/science.adh8697,Science,38815010,https://pubmed.ncbi.nlm.nih.gov/38815010,Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity,2024,,"Kathleen E Houlahan, Aziz Khan, Noah F Greenwald, Cristina Sotomayor Vivas, Robert B West, Michael Angelo, Christina Curtis","Tumors with the same diagnosis can have different molecular profiles and response to treatment. It remains unclear when and why these differences arise. Somatic genomic aberrations occur within the context of a highly variable germline genome. Interrogating 5870 breast cancer lesions, we demonstrated that germline-derived epitopes in recurrently amplified genes influence somatic evolution by mediating immunoediting. Individuals with a high germline-epitope burden in human epidermal growth factor receptor 2 (HER2/ERBB2) are less likely to develop HER2-positive breast cancer compared with other subtypes. The same holds true for recurrent amplicons defining three aggressive estrogen receptor (ER)-positive subgroups. Tumors that overcome such immune-mediated negative selection are more aggressive and demonstrate an ""immune cold"" phenotype. These data show that the germline genome plays a role in dictating somatic evolution.",RNA Sequencing,Breast Carcinoma,Breast,,Open Access +PublicationView,CA209975,CSBC,"Metastasis, Tumor-Immune, Drug Resistance/Sensitivity, Microenvironment",https://doi.org/10.1038/s41586-024-08150-0,Nature,39478232,https://pubmed.ncbi.nlm.nih.gov/39478232,Progressive plasticity during colorectal cancer metastasis,2024,,"A R Moorman, E K Benitez, F Cambuli, Q Jiang, A Mahmoud, M Lumish, S Hartner, S Balkaran, J Bermeo, S Asawa, C Firat, A Saxena, F Wu, A Luthra, C Burdziak, Y Xie, V Sgambati, K Luckett, Y Li, Z Yi, I Masilionis, K Soares, E Pappou, R Yaeger, P Kingham, W Jarnagin, P Paty, M R Weiser, L Mazutis, M D'Angelica, J Shia, J Garcia-Aguilar, T Nawy, T J Hollmann, R Chaligné, F Sanchez-Vega, R Sharma, D Pe'er, K Ganesh","As cancers progress, they become increasingly aggressive-metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death1,2. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance3-5. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1 as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1 licenses non-canonical reprogramming.","Single Cell RNA-Sequencing, Mathematical Modeling",Pan-cancer,Not Applicable,,Open Access +PublicationView,CA214282,PS-ON,"Evolution, Heterogeneity",https://doi.org/10.1091/mbc.e24-04-0188,Mol Biol Cell,39292916,https://pubmed.ncbi.nlm.nih.gov/39292916,RAD51 regulates eukaryotic chromatin motions in the absence of DNA damage,2024,,"Amine Maarouf, Fadil Iqbal, Sarvath Sanaullah, Maëlle Locatelli, Andrew T Atanasiu, Daniel Kolbin, Chloé Hommais, Joëlle K Mühlemann, Keith Bonin, Kerry Bloom, Jing Liu, Pierre-Alexandre Vidi","In yeasts and higher eukaryotes, chromatin motions may be tuned to genomic functions, with transcriptional activation and the DNA damage response both leading to profound changes in chromatin dynamics. The RAD51 recombinase is a key mediator of chromatin mobility following DNA damage. As functions of RAD51 beyond DNA repair are being discovered, we asked whether RAD51 modulates chromatin dynamics in the absence of DNA damage and found that inhibition or depletion of RAD51 alters chromatin motions in undamaged cells. Inhibition of RAD51 increased nucleosome clustering. Predictions from polymer models are that chromatin clusters reduce chain mobility and, indeed, we measured reduced motion of individual chromatin loci in cells treated with a RAD51 inhibitor. This effect was conserved in mammalian cells, yeasts, and plant cells. In contrast, RAD51 depletion or inhibition increased global chromatin motions at the microscale. The results uncover a role for RAD51 in regulating local and global chromatin dynamics independently from DNA damage and highlight the importance of considering different physical scales when studying chromatin dynamics.","Fluorescence Imaging, Western Blotting, Cell Viability Assay",Pan-cancer,Not Applicable,,Open Access +PublicationView,CA274492,CSBC,"Tumor-Immune, Immunotherapy, Computational Model Development",https://doi.org/10.1038/s41467-024-55287-7,Nat Commun,39746987,https://pubmed.ncbi.nlm.nih.gov/39746987,A Bayesian active learning platform for scalable combination drug screens,2025,,"Christopher Tosh, Mauricio Tec, Jessica B White, Jeffrey F Quinn, Glorymar Ibanez Sanchez, Paul Calder, Andrew L Kung, Filemon S Dela Cruz, Wesley Tansey","Large-scale combination drug screens are generally considered intractable due to the immense number of possible combinations. Existing approaches use ad hoc fixed experimental designs then train machine learning models to impute unobserved combinations. Here we propose BATCHIE, an orthogonal approach that conducts experiments dynamically in batches. BATCHIE uses information theory and probabilistic modeling to design each batch to be maximally informative based on the results of previous experiments. On retrospective experiments from previous large-scale screens, BATCHIE designs rapidly discover highly effective and synergistic combinations. In a prospective combination screen of a library of 206 drugs on a collection of pediatric cancer cell lines, the BATCHIE model accurately predicts unseen combinations and detects synergies after exploring only 4% of the 1.4M possible experiments. Further, the model identifies a panel of top combinations for Ewing sarcomas, which follow-up validation experiments confirm to be effective, including the rational and translatable top hit of PARP plus topoisomerase I inhibition. These results demonstrate that adaptive experiments can enable large-scale unbiased combination drug screens with a relatively small number of experiments. BATCHIE is open source and publicly available ( https://github.com/tansey-lab/batchie ).","Mathematical Modeling, Artificial Intelligence",Pan-cancer,Not Applicable,,Open Access +PublicationView,CA268069,CCBIR,"Platform Development, Tumor-Immune, Immunotherapy, Microenvironment",https://doi.org/10.1242/jcs.262322,J Cell Sci,39475207,https://pubmed.ncbi.nlm.nih.gov/39475207,The crucial role of bioimage analysts in scientific research and publication,2024,"Training, Bioimaging, Bioimage Analysis, Bioimage Analysts","Beth A Cimini, Peter Bankhead, Rocco D'Antuono, Elnaz Fazeli, Julia Fernandez-Rodriguez, Caterina Fuster-Barceló, Robert Haase, Helena Klara Jambor, Martin L Jones, Florian Jug, Anna H Klemm, Anna Kreshuk, Stefania Marcotti, Gabriel G Martins, Sara McArdle, Kota Miura, Arrate Muñoz-Barrutia, Laura C Murphy, Michael S Nelson, Simon F Nørrelykke, Perrine Paul-Gilloteaux, Thomas Pengo, Joanna W Pylvänäinen, Lior Pytowski, Arianna Ravera, Annika Reinke, Yousr Rekik, Caterina Strambio-De-Castillia, Daniel Thédié, Virginie Uhlmann, Oliver Umney, Laura Wiggins, Kevin W Eliceiri","Bioimage analysis (BIA), a crucial discipline in biological research, overcomes the limitations of subjective analysis in microscopy through the creation and application of quantitative and reproducible methods. The establishment of dedicated BIA support within academic institutions is vital to improving research quality and efficiency and can significantly advance scientific discovery. However, a lack of training resources, limited career paths and insufficient recognition of the contributions made by bioimage analysts prevent the full realization of this potential. This Perspective - the result of the recent The Company of Biologists Workshop 'Effectively Communicating Bioimage Analysis', which aimed to summarize the global BIA landscape, categorize obstacles and offer possible solutions - proposes strategies to bring about a cultural shift towards recognizing the value of BIA by standardizing tools, improving training and encouraging formal credit for contributions. We also advocate for increased funding, standardized practices and enhanced collaboration, and we conclude with a call to action for all stakeholders to join efforts in advancing BIA.","Imaging, Mathematical Modeling",Pan-cancer,Not Applicable,,Open Access +PublicationView,CA217376,CSBC,"Evolution, Epigenetics, Heterogeneity, Microenvironment",https://doi.org/10.1016/j.ccell.2021.09.002,Cancer Cell,34597592,https://pubmed.ncbi.nlm.nih.gov/34597592,Evolution's cartographer: Mapping the fitness landscape in cancer,2021,,"Calum Gabbutt, Trevor A Graham","Cancer treatment effectiveness could be improved if it were possible to accurately anticipate the response of the tumor to treatment. Writing in Nature, Salehi et al. combine single-cell genomics and mathematical modeling to measure cancer subclone fitness and use these measurements to accurately predict the future trajectory of cancer evolution.",Mathematical Modeling,Pan-cancer,Not Applicable,,Open Access +PublicationView,CA224012,PDMC,"Drug Resistance/Sensitivity, Heterogeneity, Experimental Model Development",https://doi.org/10.1080/15384047.2024.2421584,Cancer Biol Ther,39513592,https://pubmed.ncbi.nlm.nih.gov/39513592,The polymeric fluoropyrimidine CF10 overcomes limitations of 5-FU in pancreatic ductal adenocarcinoma cells through increased replication stress,2024,"DNA damage, Pancreatic cancer, Fluoropyrimidine, Replication Stress, Pdac","Jennifer M Finan, Roberto Di Niro, Soon Young Park, Kang Jin Jeong, Madeline D Hedberg, Alexander Smith, Grace A McCarthy, Alex O Haber, John Muschler, Rosalie C Sears, Gordon B Mills, William H Gmeiner, Jonathan R Brody","Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease soon to become the second leading cause of cancer deaths in the US. Beside surgery, current therapies have narrow clinical benefits with systemic toxicities. FOLFIRINOX is the current standard of care, one component of which is 5- Fluorouracil (5-FU), which causes serious gastrointestinal and hematopoietic toxicities and is vulnerable to resistance mechanisms. Recently, we have developed polymeric fluoropyrimidines (F10, CF10) which unlike 5-FU, are, in principle, completely converted to the thymidylate synthase inhibitory metabolite FdUMP, without generating appreciable levels of ribonucleotides that cause systemic toxicities while displaying much stronger anti-cancer activity. Here, we confirm the potency of CF10 and investigate enhancement of its efficacy through combination with inhibitors in vitro targeting replication stress, a hallmark of PDAC cells. CF10 is 308-times more potent as a single agent than 5-FU and was effective in the nM range in primary patient derived models. Further, we find that activity of CF10, but not 5-FU, is enhanced through combination with inhibitors of ATR and Wee1 that regulate the S and G2 DNA damage checkpoints and can be reversed by addition of dNTPs indicative of CF10 acting, at least in part, through inducing replication stress. Our results indicate CF10 has the potential to supersede the established benefit of 5-FU in PDAC treatment and indicate novel combination approaches that should be validated in vivo and may be beneficial in established regimens that include 5-FU.","Western Blotting, Cell Viability Assay",Pancreatic Ductal Adenocarcinoma,Pancreas,,Open Access +PublicationView,CA223976,PDMC,"Microenvironment, Experimental Model Development",https://doi.org/10.3390/cells13231995,Cells,39682742,https://pubmed.ncbi.nlm.nih.gov/39682742,A High-Throughput Neurosphere-Based Colony Formation Assay to Test Drug and Radiation Sensitivity of Different Patient-Derived Glioblastoma Lines,2024,"Colony formation assay, Glioblastoma, Radiation Sensitivity, Clonogenic Assay, Brain Tumor Initiating Cells, Patient-derived Cancer Cells","Manoj Kumar, Lauren C Nassour-Caswell, Hasan Alrefai, Joshua C Anderson, Taylor L Schanel, Patricia H Hicks, Rex Cardan, Christopher D Willey","The gold standard assay for radiation response is the clonogenic assay, a normalized colony formation assay (CFA) that can capture a broad range of radiation-induced cell death mechanisms. Traditionally, this assay relies on two-dimensional (2D) cell culture conditions with colonies counted by fixing and staining protocols. While some groups have converted these to three-dimensional (3D) conditions, these models still utilize 2D-like media compositions containing serum that are incompatible with stem-like cell models such as brain tumor initiating cells (BTICs) that form self-aggregating spheroids in neural stem cell media. BTICs are the preferred patient-derived model system for studying glioblastoma (GBM) as they tend to better retain molecular and phenotypic characteristics of the original tumor tissue. As such, it is important that preclinical radiation studies should be adapted to BTIC conditions. In this study, we describe a series of experimental approaches for performing CFA experiments with BTIC cultures. Our results indicate that serum-free clonogenic assays are feasible for combination drug and radiation testing and may better facilitate translatability of preclinical findings.",Viral Transduction,Glioblastoma,Brain,,Open Access +PublicationView,CA217376,CSBC,"Evolution, Epigenetics, Heterogeneity, Microenvironment",https://doi.org/10.1038/s41568-024-00734-2,Nat Rev Cancer,39256635,https://pubmed.ncbi.nlm.nih.gov/39256635,The evolutionary theory of cancer: challenges and potential solutions,2024,,"Lucie Laplane, Carlo C Maley","The clonal evolution model of cancer was developed in the 1950s-1970s and became central to cancer biology in the twenty-first century, largely through studies of cancer genetics. Although it has proven its worth, its structure has been challenged by observations of phenotypic plasticity, non-genetic forms of inheritance, non-genetic determinants of clone fitness and non-tree-like transmission of genes. There is even confusion about the definition of a clone, which we aim to resolve. The performance and value of the clonal evolution model depends on the empirical extent to which evolutionary processes are involved in cancer, and on its theoretical ability to account for those evolutionary processes. Here, we identify limits in the theoretical performance of the clonal evolution model and provide solutions to overcome those limits. Although we do not claim that clonal evolution can explain everything about cancer, we show how many of the complexities that have been identified in the dynamics of cancer can be integrated into the model to improve our current understanding of cancer.",Mathematical Modeling,Pan-cancer,Not Applicable,,Open Access +PublicationView,CA209992,CSBC,"Metastasis, Microenvironment",https://doi.org/10.1038/s41467-024-53228-y,Nat Commun,39523366,https://pubmed.ncbi.nlm.nih.gov/39523366,Mechanical power is maximized during contractile ring-like formation in a biomimetic dividing cell model,2024,,"Ryota Sakamoto, Michael P Murrell","The spatial and temporal dynamics of forces in cells coordinate essential behaviors like division, polarization, and migration. While intracellular signaling initiates contractile ring assembly during cell division, how mechanical forces coordinate division and their energetic costs remain unclear. Here, we develop an in vitro model where myosin-induced stress drives division-like shape changes in giant unilamellar vesicles (GUVs, liposomes). Myosin activity is controlled by light patterns globally or locally at the equator. Global activation causes slow, shallow cleavage furrows due to a tug-of-war between the equatorial and polar forces. By contrast, local activation leads to faster, deeper, and symmetric division as equatorial forces dominate. Dissociating the actin cortex at the poles is crucial for inducing significant furrowing. During furrowing, actomyosin flows align actin filaments parallel to the division plane, forming a contractile ring-like structure. Mechanical power is not greatest during contraction, but is maximized just before furrowing. This study reveals the quantitative relationship between force patterning and mechanical energy during division-like shape changes, providing insights into cell division mechanics.","Fluorescence Imaging, Mathematical Modeling",Pan-cancer,Not Applicable,,Open Access +PublicationView,CA268069,CCBIR,"Platform Development, Tumor-Immune, Immunotherapy, Microenvironment",https://doi.org/10.1016/j.adro.2024.101677,Adv Radiat Oncol,39703718,https://pubmed.ncbi.nlm.nih.gov/39703718,Effect of External Beam Radiation Therapy and Brachytherapy on Circulating Myeloid-Derived Suppressor Cell Populations in Patients Treated Definitively for Cervical Cancer,2025,,"Kelsey M Wanhainen, Matthew Berkseth, Nicole Sando, Lydia Golden, Amy Techam, Jennifer Wieworka, Kyra M Boorsma Bergerud, Peter Argenta, Andrea O'Shea, Britt K Erickson, Sally Mullany, Colleen Rivard, Rahel Ghebre, Deanna Teoh, Margaret Reynolds, Stephanie Terezakis, Jianling Yuan, Lindsey Sloan","Purpose: The immunosuppressive function of myeloid-derived suppressor cells (MDSCs) has been implicated in the regulation of immune responses against cancer and is associated with poor prognosis. Radiation treatment is known to alter immune cell populations within the tumor; however, whether this results in the recruitment of immunosuppressive MDSC populations is not well understood. Here we evaluate the response of circulating MDSC populations in patients treated per standard-of-care cisplatin chemoradiation therapy (CRT) for locally invasive cervical cancer. Methods and materials: Newly diagnosed, treatment-naïve patients with locally advanced cervical cancer were enrolled. Blood samples were collected from patients prior to starting CRT (T0), after external beam radiation therapy (T1), and after high-dose-rate brachytherapy (T2). Samples from each time point were processed, and the prevalence of MDSC subsets was determined using flow cytometry. MDSC populations were identified using Live/Dead-CD11b+CD33+HLA-DR- staining. MDSC subsets were further subdivided into granulocytic (g-, CD15+CD14-), monocytic (m-, CD15-CD14+), or early-MDSCs (e-, CD15-CD14-). Results: Most patients in our study were Caucasian nonsmokers with human papillomavirus-associated squamous cell carcinoma of the cervix. We saw a trend for increased MDSC frequency in patients with more advanced-stage disease at the time of initiating treatment. MDSCs increase in response to CRT and peak after brachytherapy (T2). In particular, the g-MDSC subset increases by 6.44 times relative to the baseline. There was no correlation between MDSC expansion and response to therapy. Conclusion: Our study confirms other reports that circulating MDSCs in patients with cervical cancer increase in response to CRT and are associated with more advanced stages. Additionally, we show that MDSC expansion is driven by the g-MDSC subset. We did not see any correlation between MDSC expansion and treatment response, though this may be because of the limited sample size for this study.",Clinical Study,Cervical Carcinoma,Cervix Uteri,,Open Access +PublicationView,CA210152,PS-ON,"Metastasis, Microenvironment",https://doi.org/10.1172/jci170953,J Clin Invest,39480488,https://pubmed.ncbi.nlm.nih.gov/39480488,Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels,2024,"Bone marrow, Breast cancer, Bioinformatics, Oncology","Saptarshi Sinha, Brennan W Callow, Alex P Farfel, Suchismita Roy, Siyi Chen, Maria Masotti, Shrila Rajendran, Johanna M Buschhaus, Celia R Espinoza, Kathryn E Luker, Pradipta Ghosh, Gary D Luker","Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between ""borrowed"" and ""intrinsic"" components. Bioinformatics prioritized one of the borrowed components, CCDC88A/GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced approximately 20% of both the borrowed and the intrinsic gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.","RNA Sequencing, Murine Model",Breast Carcinoma,Breast,,Open Access +PublicationView,CA223976,PDMC,"Microenvironment, Experimental Model Development",https://doi.org/10.1016/j.radonc.2024.110646,Radiother Oncol,39579870,https://pubmed.ncbi.nlm.nih.gov/39579870,Altering fractionation during radiation overcomes radio-resistance in patient-derived glioblastoma cells assessed using a novel longitudinal radiation cytotoxicity assay,2025,"Cell viability, Radiosensitivity, Glioblastoma, xenograft, Btic","Lauren C Nassour-Caswell, Manoj Kumar, Christian T Stackhouse, Hasan Alrefai, Taylor L Schanel, Benjamin M Honan, Andee M Beierle, Patricia H Hicks, Joshua C Anderson, Christopher D Willey, Jeffrey S Peacock","Purpose: Current radiotherapy (RT) in glioblastoma (GBM) is delivered as constant dose fractions (CDF), which do not account for intratumoral-heterogeneity and radio-selection in GBM. These factors contribute to differential treatment response complicating the therapeutic efficacy of this principle. Our study aims to investigate an alternative dosing strategy to overcome radio-resistance using a novel longitudinal radiation cytotoxicity assay. Methods: Theoretical In-silico mathematical assumptions were combined with an in-vitro experimental strategy to investigate alternative radiation regimens. Patient-derived xenograft (PDX) brain tumor-initiating cells (BTICs) with differential radiation-sensitivities were tested individually with sham control and three regimens of the same nominal and average dose of 16 Gy (over four fractions), but with altered doses per fraction. Fractions were delivered conventionally (CDF: 4, 4, 4, 4 Gy), or as dynamic dose fractions (DDF) ""ramped down"" (RD: 7, 5, 3, 1 Gy), or DDF ""ramped up"" (RU: 1, 3, 5, 7 Gy), every 4 days. Interfraction-longitudinal data were collected by imaging cells every 5 days, and endpoint viability was taken on day 20. Results: The proposed method of radiosensitivity assessment allows for longitudinal-interfraction investigation in addition to endpoint analysis. Delivering four-fraction doses in an RD manner proves to be most effective at overcoming acquired radiation resistance in BTICs (Relative cell viability: CDF vs. RD: P < 0.0001; Surviving fraction: CDF: vs. RD: P < 0.0001). Conclusions: Using in-silico cytotoxicity prediction modeling and an altered radiosensitivity assessment, we show DDF-RD is effective at inducing cytotoxicity in three BTIC lines with differential radiosensitivity.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,"CA245313, CA274509, CA268083","CSBC, TEC, CCBIR","Method/Assay Development, Immunotherapy, Metastasis, Microenvironment, Drug Resistance/Sensitivity, Computational Model Development",https://doi.org/10.1038/s41592-024-02533-x,Nat Methods,39643677,https://pubmed.ncbi.nlm.nih.gov/39643677,Integrative spatial protein profiling with multi-omics,2024,,Rong Fan,No abstract available.,Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA209891,CSBC,"Evolution, Drug Resistance/Sensitivity, Heterogeneity",https://doi.org/10.1158/0008-5472.can-24-0456,Cancer Res,39652575,https://pubmed.ncbi.nlm.nih.gov/39652575,HBV Remodels PP2A Complexes to Rewire Kinase Signaling in Hepatocellular Carcinoma,2024,,"Rigney E Turnham, Adriana Pitea, Gwendolyn M Jang, Zhong Xu, Huat Chye Lim, Alex L Choi, John Von Dollen, Rebecca S Levin, James T Webber, Elizabeth McCarthy, Junjie Hu, Xiaolei Li, Li Che, Ananya Singh, Alex Yoon, Gary Chan, Robin K Kelley, Danielle L Swaney, Wei Zhang, Sourav Bandyopadhyay, Fabian J Theis, Manon Eckhardt, Xin Chen, Kevan M Shokat, Trey Ideker, Nevan J Krogan, John D Gordan","Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite the primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in HCC, suggesting that it impacts the biology of established HCC. Characterization of the interaction of HBV with host proteins and the mechanistic contributions of HBV to HCC initiation and maintenance could provide insights into HCC biology and uncover therapeutic vulnerabilities. Here, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human proteins in hepatocellular carcinoma (HCC). A subset of the host factors targeted by HBV proteins were preferentially mutated in non-HBV-associated HCC, suggesting that their interaction with HBV influences HCC biology. HBV interacted with proteins involved in mRNA splicing, mitogenic signaling, and DNA repair, with the latter set interacting with the HBV oncoprotein X (HBx). HBx remodeled the PP2A phosphatase complex by excluding striatin regulatory subunits from the PP2A holoenzyme, and the HBx effects on PP2A caused Hippo kinase activation. In parallel, HBx activated mTOR complex 2 (mTORC2), which can prevent YAP degradation. mTORC2-mediated upregulation of YAP was observed in human HCC specimens and mouse HCC models and could be targeted with mTOR kinase inhibitors. Thus, HBV interaction with host proteins rewires HCC signaling rather than directly activating mitogenic pathways, provide an alternative paradigm for the cellular effects of a tumor promoting virus.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,"CA250481, CA220378","PS-ON, CSBC","Evolution, Tumor-Immune, Heterogeneity",https://doi.org/10.1148/radiol.232555,Radiology,39656118,https://pubmed.ncbi.nlm.nih.gov/39656118,The QIBA Profile for Dynamic Susceptibility Contrast MRI Quantitative Imaging Biomarkers for Assessing Gliomas,2024,,"Mark S Shiroishi, Bradley J Erickson, Leland S Hu, Daniel P Barboriak, Lino Becerra, Laura C Bell, Michael A Boss, Jerrold L Boxerman, Steven Cen, Lisa Cimino, Zhaoyang Fan, Kathryn E Keenan, John E Kirsch, Nima Ameli, Sina Nazemi, C Chad Quarles, Mark A Rosen, Luis Rodriguez, Kathleen M Schmainda, Gudrun Zahlmann, Yuxiang Zhou, Nancy Obuchowski, Ona Wu, None None","The dynamic susceptibility contrast (DSC) MRI measures of relative cerebral blood volume (rCBV) play a central role in monitoring therapeutic response and disease progression in patients with gliomas. Previous investigations have demonstrated promise of using rCBV in classifying tumor grade, elucidating tumor viability after therapy, and differentiating pseudoprogression and pseudoresponse. However, the quantification and reproducibility of rCBV measurements across patients, devices, and software remain a critical barrier to routine or clinical trial use of longitudinal DSC MRI in patients with gliomas. To address this limitation, the RSNA DSC MRI Biomarker Committee of the Quantitative Imaging Biomarkers Alliance developed a Profile that defines statistics-based claims for the precision of longitudinal measurements. Although rCBV is the clinical marker of interest, the Profile focused on the reproducibility of the measured quantitative imaging biomarker, which is the area under the contrast agent concentration-time curve (AUC) normalized by the mean value of normal-appearing contralateral white matter tissue (tissue-normalized AUC values). Based on previous reports of within-subject coefficient of variation (wCV) in the tissue-normalized AUC values for enhancing gliomas (wCV = 0.31), an increase of 182% or more with respect to the baseline tissue-normalized AUC value indicates that an increase has occurred with 95% confidence. In contrast, a decrease of 64% or more with respect to baseline suggests that a decrease has occurred with 95% confidence. Similarly, an increase of 399% or more in the tissue-normalized AUC values in normal brain gray matter tissue (wCV = 0.40) suggests that an increase has occurred with 95% confidence, whereas a decrease of 80% or more with respect to baseline suggests that a decrease has occurred with 95% confidence. This article provides the rationale for these claims and the compliance activities needed to achieve these claims. Potential updates to incorporate new data based on advances in technology and clinical care in the Profile are also discussed.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA244100,PS-ON,"Tumor-Immune, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.jcyt.2024.08.002,Cytotherapy,39243253,https://pubmed.ncbi.nlm.nih.gov/39243253,Expansion of tumor-infiltrating and marrow-infiltrating lymphocytes from pediatric malignant solid tumors,2025,"Immunotherapy, Pediatrics, Solid Tumors, Cellular Therapy, Tumor-infiltrating Lymphocytes","Jonathan Metts, Madeline Rodriguez-Valentin, Jonathan Hensel, Alex Alfaro, Christopher W Snyder, Odion Binitie, Caroline Chebli, Hector Monforte, Shari Pilon-Thomas, John Mullinax","Introduction: The expansion of tumor-infiltrating lymphocytes (TIL) for adoptive cellular therapy is under investigation in many solid tumors of adulthood. Marrow-infiltrating lymphocytes (MIL) have demonstrated antitumor reactivity preclinically. Successful expansion of TIL/MIL has not been reported across pediatric solid tumor histologies. The objective of this study was to demonstrate successful expansion of TIL from pediatric solid tumors for translation in an adoptive cell therapy (ACT) treatment strategy. Methods: A prospective study of TIL/MIL expansion was performed on solid tumors of pediatric patients undergoing standard-of-care procedures. TIL/MIL expansions were performed in the presence of high-dose interleukin 2. To demonstrate a full-scale expansion to clinically-relevant cell doses for TIL therapy, initial TIL culture was followed by a rapid expansion protocol for select patients. Expanded specimens were analyzed for phenotype by flow cytometry and for anti-tumor reactivity by the interferon-gamma release assay. Results: Eighteen tumor samples were obtained. Initial TIL cultures were successfully generated from 14/18 samples (77.7%). A median of 5.52 × 107 (range: 2.5 × 106-3.23 × 108) cells were produced from initial cultures, with 46.9% expressing a CD3 phenotype (46.9%). Eight samples underwent rapid expansion, demonstrating a median 458-fold expansion and a CD3 phenotype of 98%. Initial MIL cultures were successfully generated from five samples, with a predominantly CD3 phenotype (45.2%). Sufficient tumor tissue was only available for seven TIL samples to be tested for reactivity; none demonstrated responsiveness to autologous tumor. Conclusions: TIL and MIL expansion from pediatric solid tumors was successful, including the full-scale expansion process. This data supports translation to an ACT-TIL treatment strategy in the pediatric population and thus a Phase I trial of ACT-TIL in pediatric high-risk solid tumors is planned.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access \ No newline at end of file diff --git a/annotations/input/nov_datasets.csv b/annotations/input/nov_datasets.csv new file mode 100644 index 00000000..cd53ba0b --- /dev/null +++ b/annotations/input/nov_datasets.csv @@ -0,0 +1,18 @@ +Component,DatasetView_id,Dataset Pubmed Id,Dataset Grant Number,Dataset Name,Dataset Alias,Dataset Description,Dataset Design,Dataset Assay,Dataset Species,Dataset Tumor Type,Dataset Tissue,Dataset Url,Dataset File Formats,Id,entityId +DatasetView,,39333113,CA217297,3D chromatin architecture of drug-tolerant cancer cells at single-cell resolution [scHi-C],GSE194308,"Anticancer drug therapy generally elicits the drug tolerance after long-term treatment. Recent studies suggested that 3D chromatin structures of cancer cells were intimately linked to drug resistance. However, 3D chromatin structures in drug-tolerant cancer cells at single-cell resolution haven’t been elucidated. Here we performed single-cell Hi-C (scHi-C) analysis to examine the 3D chromatin structures in three stages of breast cancer cells.","To fully understand the 3D chromatin structures of drug-tolerant cancer cells at single-cell resolution, we designed scHi-C approach for analyzing a breast cancer cell model system, MCF7, MCF7M1 and MCF7TR cells. A total of 293 cells (89 MCF7 cells, 91 MCF7M1 cells, 113 MCF7TR cells) were used for scHi-C profiling.","Computational Modeling, Single Cell RNA-Sequencing",Human,Breast Carcinoma,Breast,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE194308,,, +DatasetView,,39333113,CA217297,3D chromatin architecture of drug-tolerant cancer cells at single-cell resolution (scRNA-seq dataset),GSE195610,"Anticancer drug therapy generally elicits the drug tolerance after long-term treatment. Recent studies suggested that 3D chromatin structures of cancer cells were intimately linked to drug resistance. However, 3D chromatin structures in drug-tolerant cancer cells at single-cell resolution haven’t been elucidated. Here we performed single-cell Hi-C (scHi-C) analysis to examine the 3D chromatin structures in three stages of breast cancer cells. Then Single-cell RNA-seq data were integrated with scHi-C data.","To fully understand the 3D chromatin structures of drug-tolerant cancer cells at single-cell resolution, we designed scHi-C approach for analyzing a breast cancer cell model system, MCF7, MCF7M1 and MCF7TR cells. A total of 293 cells (89 MCF7 cells, 91 MCF7M1 cells, 113 MCF7TR cells) were used for scHi-C profiling and 22,425 cells (6,172 MCF7 cells, 10,156 MCF7M1 cells, 6,097 MCF7TR cells) were used for single-cell RNA-seq (scRNA-seq) profiling . This is the dataset stored for scRNA-seq data.","Computational Modeling, Single Cell RNA-Sequencing",Human,Breast Carcinoma,Breast,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE195610,,, +DatasetView,,39333113,CA217297,3D chromatin architecture of drug-tolerant cancer cells at single-cell resolution,GSE195611,This SuperSeries is composed of the SubSeries listed below.,Refer to individual Series,"Computational Modeling, Single Cell RNA-Sequencing",Human,Breast Carcinoma,Breast,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE195611,,, +DatasetView,,39333113,CA217297,3D chromatin architecture of drug-tolerant cancer cells at single-cell resolution (Reference dataset of population cells.,GSE195810,"Anticancer drug therapy generally elicits the drug tolerance after long-term treatment. Recent studies suggested that 3D chromatin structures of cancer cells were intimately linked to drug resistance. However, 3D chromatin structures in drug-tolerant cancer cells at single-cell resolution haven’t been elucidated. Here we performed single-cell Hi-C (scHi-C) analysis to examine the 3D chromatin structures in three stages of breast cancer cells. Population cells Hi-C data as the reference.","To fully understand the 3D chromatin structures of drug-tolerant cancer cells at single-cell resolution, we designed scHi-C approach for analyzing a breast cancer cell model system, MCF7, MCF7M1 and MCF7TR cells. A total of 293 cells (89 MCF7 cells, 91 MCF7M1 cells, 113 MCF7TR cells) were used for scHi-C profiling. Population cells Hi-C data as the reference. This is the dataset stored for population cells.","Computational Modeling, Single Cell RNA-Sequencing",Human,Breast Carcinoma,Breast,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE195810,,, +DatasetView,,39333113,CA217297,3D chromatin architecture of drug-tolerant cancer cells at single-cell resolution (scDNA-seq dataset),GSE239435,"Anticancer drug therapy generally elicits the drug tolerance after long-term treatment. Recent studies suggested that 3D chromatin structures of cancer cells were intimately linked to drug resistance. However, 3D chromatin structures in drug-tolerant cancer cells at single-cell resolution haven’t been elucidated. Here we performed single-cell Hi-C (scHi-C) analysis to examine the 3D chromatin structures in three stages of breast cancer cells. Then Single-cell RNA-seq data were integrated with scHi-C data. scDNA-seq data were also been generated.","To fully understand the 3D chromatin structures of drug-tolerant cancer cells at single-cell resolution, we designed scHi-C approach for analyzing a breast cancer cell model system, MCF7, MCF7M1 and MCF7TR cells. A total of 293 cells (89 MCF7 cells, 91 MCF7M1 cells, 113 MCF7TR cells) were used for scHi-C profiling and 22,425 cells (6,172 MCF7 cells, 10,156 MCF7M1 cells, 6,097 MCF7TR cells) were used for single-cell RNA-seq (scRNA-seq) profiling . Total of 105 cells (33 of MCF7 cells, 33 of MCF7M1 and 39 of MCFTR cells) were used for single-cell DNA-seq (scDNA-seq) profiling This is the dataset stored for scDNA-seq data.","Computational Modeling, Single Cell RNA-Sequencing",Human,Breast Carcinoma,Breast,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE239435,,, +DatasetView,,38823395,CA225088,A myeloid maturation program initiated by nucleotide depletion during S phase [CRISPRi screen],GSE211065,"Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.","Genome-wide and sublibrary CRISPRi screens were performed in ER-Hoxa9, THP-1, and K562 cells with and without BRQ treatment.",Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE211065,,, +DatasetView,,38823395,CA225089,Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress,GSE172335,This SuperSeries is composed of the SubSeries listed below.,Refer to individual Series,Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE172335,,, +DatasetView,,38823395,CA225090,A myeloid maturation program initiated by nucleotide depletion during S phase [Cut & Run],GSE172296,"Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.","Cell lines were treated with vehicle or drug for the indicated time, and CUT&RUN was performed with the indicated antibodies.",Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE172296,,, +DatasetView,,38823395,CA225091,A myeloid maturation program initiated by nucleotide depletion during S phase [ATAC-Seq],GSE172299,"Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.",Cell lines were treated with vehicle or drug for the indicated times and ATACseq was performed.,Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE172299,,, +DatasetView,,38823395,CA225092,A myeloid maturation program initiated by nucleotide depletion during S phase [ery_scrnaseq],GSE262392,"Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.","scRNAseq was performed on erythroid progenitors differentiated from human CD34+ HSPCs at day 11 and 14; they were treated with DMSO, HU, or APH starting at day 7.",Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE262392,,, +DatasetView,,38823395,CA225093,A myeloid maturation program initiated by nucleotide depletion during S phase [scRNA-seq],GSE172300,"Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.","Cell lines were treated with vehicle or drug for the indicated times and barcoded with MULTI-seq, and single-cell transcriptomes were sequenced on the 10X Genomics platform.",Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE172300,,, +DatasetView,,38823395,CA225094,A myeloid maturation program initiated by nucleotide depletion during S phase [RNA-Seq],GSE172333,"Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.","Cell lines were treated with vehicle or drug for the indicated times, RNA was extracted, and RNA sequencing was performed.",Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE172333,,, +DatasetView,,39058094,CA224013,MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer [RNA-seq],GSE242516,The effect of gene perturbation on the transcriptome was evaluated in human Cas9 expressing cancer cell lines,"Human pancreatic cancer cell lines were cultured in DMEM,RPMI or HITES supplemented with 5 or 10% fetal bovine serum (FBS). RNA-extraction (Triazol) and Poly-A followed by library preparation was performed in accordance to manufacturer’s instructions (Illumina Truseq Kit).","Western Blotting, Immunohistochemistry Staining Method, Fluorescence Microscopy, RT-qPCR, Immunoprecipitation",Human,Pan-Cancer,Not Applicable,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242516,,, +DatasetView,,39058094,CA224014,MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer,GSE242517,This SuperSeries is composed of the SubSeries listed below.,Refer to individual Series,"Western Blotting, Immunohistochemistry Staining Method, Fluorescence Microscopy, RT-qPCR, Immunoprecipitation",Human,Pan-Cancer,Not Applicable,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242517,,, +DatasetView,,39058094,CA224015,MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer [CUT&RUN],GSE241897,The effect of gene perturbation on the histone mark H3K27ac was evaluated in human Cas9 expressing MDA-MB231 cancers,Human pancreatic cancer cell lines were cultured in DMEM supplemented with 10% fetal bovine serum (FBS). CUT&RUN was performed according to manufacturer’s instructions (EpiCypher-CUTANA Kit) and Sequencing libraries were generated using Ultra II DNA Library Prep Kit (NEBNext),"Western Blotting, Immunohistochemistry Staining Method, Fluorescence Microscopy, RT-qPCR, Immunoprecipitation",Human,Pan-Cancer,Not Applicable,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE241897,,, +DatasetView,,39394434,"CA274492, CA209975",Bulk RNA-sequencing of mouse prostate tumors initiated by transplantation of engineered organoids.,GSE246251,Purpose: Profile global expression of prostatic tumors to compare with published datasets. Methods: Prostate tumors were flash frozen followed by processed for total RNA using the RNeasy kit (Qiagen). Samples were submitted for polyA library preparation and bulk RNA-sequencing. Conclusions: Global gene expression profiling and comparison of prostate tumor genotypes suggests differential enrichment of neuroendocrine signatures that match established human neuroendocrine prostate cancer expression signatures.,"To investigate the molecular landscape of transplanted PtPM and RPM orthotopic prostate tumors, n = 10 PtPM and n = 8 RPM tumors isolated at early or late time points were subjected bulk RNA-sequencing.","Murine Model, Immunohistochemistry Staining Method, RNA Sequencing",Mouse,Prostate Adenocarcinoma,Prostate Gland,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE246251,,, +DatasetView,,39330965,CA228963,HCC spatial transcriptomic profiling reveals significant and potentially targetable cancer-endothelial interactions,GSE277104,"HCC is a highly vascular tumor, and many effective drug regimens target the tumor blood vessels. Prior bulk HCC subtyping data used bulk transcriptomes, which contained a mixture of parenchymal and stromal contributions. Using cell type–specific spatial transcriptomics techniques to separate cancer cells and endothelial cells applied to a set of 41 resected HCC tissue specimens, we report that the prior Hoshida bulk transcriptional subtyping schema is driven largely by an endothelial fraction, show an alternative tumor-specific schema has potential prognostic value, and use spatially paired ligand-receptor analyses to identify known and novel (LGALS9 tumor-HAVCR2 vessel) signaling relationships that drive HCC biology in a subtype-specific and potentially targetable manner. Our study leverages spatial gene expression profiling technologies to dissect HCC heterogeneity and identify heterogeneous sig- naling relationships between cancer cells and their endothelial cells. Future validation and expansion of these findings may validate novel cancer- endothelial cell interactions and related drug targets.",We used cell type–specific spatial transcriptomics techniques (Nanostring GeoMx) to separate cancer cells and endothelial cells applied to a set of 41 resected HCC tissue specimens.,Computational Modeling,,Hepatocellular Carcinoma,Liver,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE277104,,, \ No newline at end of file diff --git a/annotations/input/nov_filepaths.csv b/annotations/input/nov_filepaths.csv new file mode 100644 index 00000000..61acd824 --- /dev/null +++ b/annotations/input/nov_filepaths.csv @@ -0,0 +1,45 @@ +File Paths,folderIdPublication +/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA274499_publication.csv,syn43447156 +/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA267170_publication.csv,syn43447074 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+/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA209891_publication.csv,syn32698008 +/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA283114_publication.csv,syn53212977 +/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA238720_publication.csv,syn32698104 +/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA232216_publication.csv,syn32698110 +/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA268069_publication.csv,syn35270515 +/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA210181_publication.csv,syn32698212 diff --git a/annotations/input/nov_pubs.csv b/annotations/input/nov_pubs.csv new file mode 100644 index 00000000..05b18fc6 --- /dev/null +++ b/annotations/input/nov_pubs.csv @@ -0,0 +1,48 @@ +Component,Publication Grant Number,Publication Consortium Name,Publication Theme Name,Publication Doi,Publication Journal,Pubmed Id,Pubmed Url,Publication Title,Publication Year,Publication Keywords,Publication Authors,Publication Abstract,Publication Assay,Publication Tumor Type,Publication Tissue,Publication Dataset Alias,Publication Accessibility +PublicationView,CA210190,PS-ON,"Microenvironment, Metastasis, Tumor-Immune",https://doi.org/10.1002/sim.10256,Stat Med,39422157,https://pubmed.ncbi.nlm.nih.gov/39422157,Phase I/II Design for Selecting Subgroup-Specific Optimal Biological Doses for Prespecified Subgroups,2024,"Immunotherapy, Subgroups, Bayesian Design, Optimal Biological Dose, Spike And Slab","Sydney Porter, Thomas A Murray, Anne Eaton","We propose a phase I/II trial design to support dose-finding when the optimal biological dose (OBD) may differ in two prespecified patient subgroups. The proposed design uses a utility function to quantify efficacy-toxicity trade-offs, and a Bayesian model with spike and slab prior distributions for the subgroup effect on toxicity and efficacy to guide dosing and to facilitate identifying either subgroup-specific OBDs or a common OBD depending on the resulting trial data. In a simulation study, we find the proposed design performs nearly as well as a design that ignores subgroups when the dose-toxicity and dose-efficacy relationships are the same in both subgroups, and nearly as well as a design with independent dose-finding within each subgroup when these relationships differ across subgroups. In other words, the proposed adaptive design performs similarly to the design that would be chosen if investigators possessed foreknowledge about whether the dose-toxicity and/or dose-efficacy relationship differs across two prespecified subgroups. Thus, the proposed design may be effective for OBD selection when uncertainty exists about whether the OBD differs in two prespecified subgroups.",,,,,Open Access +PublicationView,CA250040,PS-ON,Tumor-Immune,https://doi.org/10.1038/s41467-024-52565-2,Nat Commun,39333505,https://pubmed.ncbi.nlm.nih.gov/39333505,Mechanical force regulates ligand binding and function of PD-1,2024,,"Kaitao Li, Paul Cardenas-Lizana, Jintian Lyu, Anna V Kellner, Menglan Li, Peiwen Cong, Valencia E Watson, Zhou Yuan, Eunseon Ahn, Larissa Doudy, Zhenhai Li, Khalid Salaita, Rafi Ahmed, Cheng Zhu","Despite the success of PD-1 blockade in cancer therapy, how PD-1 initiates signaling remains unclear. Soluble PD-L1 is found in patient sera and can bind PD-1 but fails to suppress T cell function. Here, we show that PD-1 function is reduced when mechanical support on ligand is removed. Mechanistically, cells exert forces to PD-1 and prolong bond lifetime at forces <7 pN (catch bond) while accelerate dissociation at forces >8pN (slip bond). Molecular dynamics of PD-1-PD-L2 complex suggests force may cause relative rotation and translation between the two molecules yielding distinct atomic contacts not observed in the crystal structure. Compared to wild-type, PD-1 mutants targeting the force-induced distinct interactions maintain the same binding affinity but suppressed/eliminated catch bond, lowered rupture force, and reduced inhibitory function. Our results uncover a mechanism for cells to probe the mechanical support of PD-1-PD-Ligand bonds using endogenous forces to regulate PD-1 signaling.",,,,,Open Access +PublicationView,,,,https://doi.org/10.1182/bloodadvances.2023012529,Blood Adv,38324726,https://pubmed.ncbi.nlm.nih.gov/38324726,Cysteine-binding adjuvant enhances survival and promotes immune function in a murine model of acute myeloid leukemia,2024,,"Anna J Slezak, Kevin Chang, Taryn N Beckman, Kirsten C Refvik, Aaron T Alpar, Abigail L Lauterbach, Ani Solanki, Jung Woo Kwon, Suzana Gomes, Aslan Mansurov, Jeffrey A Hubbell","Abstract: Therapeutic vaccination has long been a promising avenue for cancer immunotherapy but is often limited by tumor heterogeneity. The genetic and molecular diversity between patients often results in variation in the antigens present on cancer cell surfaces. As a result, recent research has focused on personalized cancer vaccines. Although promising, this strategy suffers from time-consuming production, high cost, inaccessibility, and targeting of a limited number of tumor antigens. Instead, we explore an antigen-agnostic polymeric in situ cancer vaccination platform for treating blood malignancies, in our model here with acute myeloid leukemia (AML). Rather than immunizing against specific antigens or targeting adjuvant to specific cell-surface markers, this platform leverages a characteristic metabolic and enzymatic dysregulation in cancer cells that produces an excess of free cysteine thiols on their surfaces. These thiols increase in abundance after treatment with cytotoxic agents such as cytarabine, the current standard of care in AML. The resulting free thiols can undergo efficient disulfide exchange with pyridyl disulfide (PDS) moieties on our construct and allow for in situ covalent attachment to cancer cell surfaces and debris. PDS-functionalized monomers are incorporated into a statistical copolymer with pendant mannose groups and TLR7 agonists to target covalently linked antigen and adjuvant to antigen-presenting cells in the liver and spleen after IV administration. There, the compound initiates an anticancer immune response, including T-cell activation and antibody generation, ultimately prolonging survival in cancer-bearing mice.",,,,,Open Access +PublicationView,CA217297,CSBC,"Epigenetics, Drug Resistance/Sensitivity",https://doi.org/10.1038/s41467-024-52440-0,Nat Commun,39333113,https://pubmed.ncbi.nlm.nih.gov/39333113,Integration of scHi-C and scRNA-seq data defines distinct 3D-regulated and biological-context dependent cell subpopulations,2024,,"Yufan Zhou, Tian Li, Lavanya Choppavarapu, Kun Fang, Shili Lin, Victor X Jin","An integration of 3D chromatin structure and gene expression at single-cell resolution has yet been demonstrated. Here, we develop a computational method, a multiomic data integration (MUDI) algorithm, which integrates scHi-C and scRNA-seq data to precisely define the 3D-regulated and biological-context dependent cell subpopulations or topologically integrated subpopulations (TISPs). We demonstrate its algorithmic utility on the publicly available and newly generated scHi-C and scRNA-seq data. We then test and apply MUDI in a breast cancer cell model system to demonstrate its biological-context dependent utility. We find the newly defined topologically conserved associating domain (CAD) is the characteristic single-cell 3D chromatin structure and better characterizes chromatin domains in single-cell resolution. We further identify 20 TISPs uniquely characterizing 3D-regulated breast cancer cellular states. We reveal two of TISPs are remarkably resemble to high cycling breast cancer persister cells and chromatin modifying enzymes might be functional regulators to drive the alteration of the 3D chromatin structures. Our comprehensive integration of scHi-C and scRNA-seq data in cancer cells at single-cell resolution provides mechanistic insights into 3D-regulated heterogeneity of developing drug-tolerant cancer cells.",,,,"GSE194308, GSE195610, GSE195611, GSE195810, GSE239435",Open Access +PublicationView,CA274499,CSBC,"Oncogenic Stress, Metabolism",https://doi.org/10.1016/j.jbc.2024.105669,J Biol Chem,38272221,https://pubmed.ncbi.nlm.nih.gov/38272221,Chromosomal passenger complex condensates generate parallel microtubule bundles in vitro,2024,"Chromosomal Instability, Aurora Kinase, Mitotic Spindle, Chromosomal Passenger Complex, Mtoc, Midzone, Inner Centromere","Ewa Niedzialkowska, Tan M Truong, Luke A Eldredge, Aamir Ali, Stefanie Redemann, P Todd Stukenberg","The mitotic spindle contains many bundles of microtubules (MTs) including midzones and kinetochore fibers, but little is known about how bundled structures are formed. Here, we show that the chromosomal passenger complex (CPC) purified from Escherichia coli undergoes liquid-liquid demixing in vitro. An emergent property of the resultant condensates is to generate parallel MT bundles when incubated with free tubulin and GTP in vitro. We demonstrate that MT bundles emerge from CPC droplets with protruding minus ends that then grow into long and tapered MT structures. During this growth, we found that the CPC in these condensates apparently reorganize to coat and bundle the resulting MT structures. CPC mutants attenuated for liquid-liquid demixing or MT binding prevented the generation of parallel MT bundles in vitro and reduced the number of MTs present at spindle midzones in HeLa cells. Our data demonstrate that an in vitro biochemical activity to produce MT bundles emerges after the concentration of the CPC and provides models for how cells generate parallel-bundled MT structures that are important for the assembly of the mitotic spindle. Moreover, these data suggest that cells contain MT-organizing centers that generate MT bundles that emerge with the opposite polarity from centrosomes.",,,,,Open Access +PublicationView,CA253540,CSBC,"Heterogeneity, Drug Resistance/Sensitivity",https://doi.org/10.1038/s41540-024-00345-5,NPJ Syst Biol Appl,38365857,https://pubmed.ncbi.nlm.nih.gov/38365857,Forum on immune digital twins: a meeting report,2024,,"Reinhard Laubenbacher, Fred Adler, Gary An, Filippo Castiglione, Stephen Eubank, Luis L Fonseca, James Glazier, Tomas Helikar, Marti Jett-Tilton, Denise Kirschner, Paul Macklin, Borna Mehrad, Beth Moore, Virginia Pasour, Ilya Shmulevich, Amber Smith, Isabel Voigt, Thomas E Yankeelov, Tjalf Ziemssen","Medical digital twins are computational models of human biology relevant to a given medical condition, which are tailored to an individual patient, thereby predicting the course of disease and individualized treatments, an important goal of personalized medicine. The immune system, which has a central role in many diseases, is highly heterogeneous between individuals, and thus poses a major challenge for this technology. In February 2023, an international group of experts convened for two days to discuss these challenges related to immune digital twins. The group consisted of clinicians, immunologists, biologists, and mathematical modelers, representative of the interdisciplinary nature of medical digital twin development. A video recording of the entire event is available. This paper presents a synopsis of the discussions, brief descriptions of ongoing digital twin projects at different stages of progress. It also proposes a 5-year action plan for further developing this technology. The main recommendations are to identify and pursue a small number of promising use cases, to develop stimulation-specific assays of immune function in a clinical setting, and to develop a database of existing computational immune models, as well as advanced modeling technology and infrastructure.",,,,,Open Access +PublicationView,CA228608,PDMC,"Metastasis, Method/Assay Development",https://doi.org/10.1126/sciadv.adk8801,Sci Adv,39485847,https://pubmed.ncbi.nlm.nih.gov/39485847,Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis,2024,,"Spencer D Shelton, Sara House, Luiza Martins Nascentes Melo, Vijayashree Ramesh, Zhenkang Chen, Tao Wei, Xun Wang, Claire B Llamas, Siva Sai Krishna Venigalla, Cameron J Menezes, Gabriele Allies, Jonathan Krystkiewicz, Jonas Rösler, Sven W Meckelmann, Peihua Zhao, Florian Rambow, Dirk Schadendorf, Zhiyu Zhao, Jennifer G Gill, Ralph J DeBerardinis, Sean J Morrison, Alpaslan Tasdogan, Prashant Mishra","Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood.",,,,,Open Access +PublicationView,CA214411,TEC,"Heterogeneity, Microenvironment, Drug Resistance/Sensitivity",https://doi.org/10.1002/advs.202001447,Adv Sci (Weinh),33042756,https://pubmed.ncbi.nlm.nih.gov/33042756,Screening Cancer Immunotherapy: When Engineering Approaches Meet Artificial Intelligence,2020,"Artificial intelligence, Drug screening, Tissue engineering, Cancer Immunotherapy, High‐throughput Screening","Xingwu Zhou, Moyuan Qu, Peyton Tebon, Xing Jiang, Canran Wang, Yumeng Xue, Jixiang Zhu, Shiming Zhang, Rahmi Oklu, Shiladitya Sengupta, Wujin Sun, Ali Khademhosseini","Immunotherapy is a class of promising anticancer treatments that has recently gained attention due to surging numbers of FDA approvals and extensive preclinical studies demonstrating efficacy. Nevertheless, further clinical implementation has been limited by high variability in patient response to different immunotherapeutic agents. These treatments currently do not have reliable predictors of efficacy and may lead to side effects. The future development of additional immunotherapy options and the prediction of patient-specific response to treatment require advanced screening platforms associated with accurate and rapid data interpretation. Advanced engineering approaches ranging from sequencing and gene editing, to tumor organoids engineering, bioprinted tissues, and organs-on-a-chip systems facilitate the screening of cancer immunotherapies by recreating the intrinsic and extrinsic features of a tumor and its microenvironment. High-throughput platform development and progress in artificial intelligence can also improve the efficiency and accuracy of screening methods. Here, these engineering approaches in screening cancer immunotherapies are highlighted, and a discussion of the future perspectives and challenges associated with these emerging fields to further advance the clinical use of state-of-the-art cancer immunotherapies are provided.",,,,,Open Access +PublicationView,CA225088,CSBC,"Microenvironment, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.devcel.2024.05.010,Dev Cell,38823395,https://pubmed.ncbi.nlm.nih.gov/38823395,Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress,2024,"Metabolism, Differentiation, Nucleotides, Cancer, Replication, Hematopoiesis, Epigenetics, Cell Fate, Replication Stress, Dependencies, Cell State","Brian T Do, Peggy P Hsu, Sidney Y Vermeulen, Zhishan Wang, Taghreed Hirz, Keene L Abbott, Najihah Aziz, Joseph M Replogle, Stefan Bjelosevic, Jonathan Paolino, Samantha A Nelson, Samuel Block, Alicia M Darnell, Raphael Ferreira, Hanyu Zhang, Jelena Milosevic, Daniel R Schmidt, Christopher Chidley, Isaac S Harris, Jonathan S Weissman, Yana Pikman, Kimberly Stegmaier, Sihem Cheloufi, Xiaofeng A Su, David B Sykes, Matthew G Vander Heiden","Control of cellular identity requires coordination of developmental programs with environmental factors such as nutrient availability, suggesting that perturbing metabolism can alter cell state. Here, we find that nucleotide depletion and DNA replication stress drive differentiation in human and murine normal and transformed hematopoietic systems, including patient-derived acute myeloid leukemia (AML) xenografts. These cell state transitions begin during S phase and are independent of ATR/ATM checkpoint signaling, double-stranded DNA break formation, and changes in cell cycle length. In systems where differentiation is blocked by oncogenic transcription factor expression, replication stress activates primed regulatory loci and induces lineage-appropriate maturation genes despite the persistence of progenitor programs. Altering the baseline cell state by manipulating transcription factor expression causes replication stress to induce genes specific for alternative lineages. The ability of replication stress to selectively activate primed maturation programs across different contexts suggests a general mechanism by which changes in metabolism can promote lineage-appropriate cell state transitions.",,,,"GSE211065, GSE172335, GSE172296, GSE172299, GSE262392, GSE172300, GSE172333",Open Access +PublicationView,CA253547,CSBC,Tumor-Immune,https://doi.org/10.1158/2159-8290.cd-24-0604,Cancer Discov,39363746,https://pubmed.ncbi.nlm.nih.gov/39363746,Transforming Cancer Research through Informatics,2024,,"Juli D Klemm, Dinah S Singer, Jill P Mesirov","For more than three decades, concurrent advances in laboratory technologies and computer science have driven the rise of cancer informatics. Today, software tools for cancer research are indispensable to the entire cancer research enterprise.",,,,,Open Access +PublicationView,CA268069,CCBIR,"Immunotherapy, Microenvironment, Platform Development, Tumor-Immune",https://doi.org/10.3390/metabo14100550,Metabolites,39452931,https://pubmed.ncbi.nlm.nih.gov/39452931,Multi-Modal Investigation of Metabolism in Murine Breast Cancer Cell Lines Using Fluorescence Lifetime Microscopy and Hyperpolarized 13C-Pyruvate Magnetic Resonance Spectroscopy,2024,"Metabolism, Breast cancer, Metastatic potential, Flim, Mrs, Hyperpolarized, Carbon-13","Sarah Erickson-Bhatt, Benjamin L Cox, Erin Macdonald, Jenu V Chacko, Paul Begovatz, Patricia J Keely, Suzanne M Ponik, Kevin W Eliceiri, Sean B Fain","Background/Objectives: Despite the role of metabolism in breast cancer metastasis, we still cannot predict which breast tumors will progress to distal metastatic lesions or remain dormant. This work uses metabolic imaging to study breast cancer cell lines (4T1, 4T07, and 67NR) with differing metastatic potential in a 3D collagen gel bioreactor system. Methods: Within the bioreactor, hyperpolarized magnetic resonance spectroscopy (HP-MRS) is used to image lactate/pyruvate ratios, while fluorescence lifetime imaging microscopy (FLIM) of endogenous metabolites measures metabolism at the cellular scale. Results: HP-MRS results showed no lactate peak for 67NR and a comparatively large lactate/pyruvate ratio for both 4T1 and 4T07 cell lines, suggestive of greater pyruvate utilization with greater metastatic potential. Similar patterns were observed using FLIM with significant increases in FAD intensity, redox ratio, and NAD(P)H lifetime. The lactate/pyruvate ratio was strongly correlated to NAD(P)H lifetime, consistent with the role of NADH as an electron donor for the glycolytic pathway, suggestive of an overall upregulation of metabolism (both glycolytic and oxidative), for the 4T07 and 4T1 cell lines compared to the non-metastatic 67NR cell line. Conclusions: These findings support a complementary role for HP-MRS and FLIM enabled by a novel collagen gel bioreactor system to investigate metastatic potential and cancer metabolism.",,,,,Open Access +PublicationView,CA253540,CSBC,"Heterogeneity, Drug Resistance/Sensitivity",https://doi.org/10.1038/s41540-024-00441-6,NPJ Syst Biol Appl,39420005,https://pubmed.ncbi.nlm.nih.gov/39420005,Computational identification of surface markers for isolating distinct subpopulations from heterogeneous cancer cell populations,2024,,"Andrea L Gardner, Tyler A Jost, Daylin Morgan, Amy Brock","Intratumor heterogeneity reduces treatment efficacy and complicates our understanding of tumor progression and there is a pressing need to understand the functions of heterogeneous tumor cell subpopulations within a tumor, yet systems to study these processes in vitro are limited. Single-cell RNA sequencing (scRNA-seq) has revealed that some cancer cell lines include distinct subpopulations. Here, we present clusterCleaver, a computational package that uses metrics of statistical distance to identify candidate surface markers maximally unique to transcriptomic subpopulations in scRNA-seq which may be used for FACS isolation. With clusterCleaver, ESAM and BST2/tetherin were experimentally validated as surface markers which identify and separate major transcriptomic subpopulations within MDA-MB-231 and MDA-MB-436 cells, respectively. clusterCleaver is a computationally efficient and experimentally validated workflow for identification of surface markers for tracking and isolating transcriptomically distinct subpopulations within cell lines. This tool paves the way for studies on coexisting cancer cell subpopulations in well-defined in vitro systems.",,,,,Open Access +PublicationView,CA225566,PS-ON,Microenvironment,https://doi.org/10.1039/d4sm00683f,Soft Matter,39105242,https://pubmed.ncbi.nlm.nih.gov/39105242,Rethinking nuclear shaping: insights from the nuclear drop model,2024,,"Richard B Dickinson, Samere Abolghasemzade, Tanmay P Lele","Changes in the nuclear shape caused by cellular shape changes are generally assumed to reflect an elastic deformation from a spherical nuclear shape. Recent evidence, however, suggests that the nuclear lamina, which forms the outer nuclear surface together with the nuclear envelope, possesses more area than that of a sphere of the same volume. This excess area manifests as folds/wrinkles in the nuclear surface in rounded cells and allows facile nuclear flattening during cell spreading without any changes in nuclear volume or surface area. When the lamina becomes smooth and taut, it is inextensible, and supports a surface tension. At this point, it is possible to mathematically calculate the limiting nuclear shape purely based on geometric considerations. In this paper, we provide a commentary on the ""nuclear drop model"" which seeks to integrate the above features. We outline its testable physical properties and explore its biological implications.",,,,,Open Access +PublicationView,CA282451,TEC,"Microenvironment, Experimental Model Development",https://doi.org/10.1002/adhm.202402571,Adv Healthc Mater,39498750,https://pubmed.ncbi.nlm.nih.gov/39498750,3D-Printed Polymeric Biomaterials for Health Applications. ,2024,,"Yuxiang Zhu, Shenghan Guo, Dharneedar Ravichandran, Arunachalam Ramanathan, M Taylor Sobczak, Alaina F Sacco, Dhanush Patil, Sri Vaishnavi Thummalapalli, Tiffany V Pulido, Jessica N Lancaster, Johnny Yi, Jeffrey L Cornella, David G Lott, Xiangfan Chen, Xuan Mei, Yu Shrike Zhang, Linbing Wang, Xianqiao Wang, Yiping Zhao, Mohammad K Hassan, Lindsay B Chambers, Taylor G Theobald, Sui Yang, Liang Liang, Kenan Song","3D printing, also known as additive manufacturing, holds immense potential for rapid prototyping and customized production of functional health-related devices. With advancements in polymer chemistry and biomedical engineering, polymeric biomaterials have become integral to 3D-printed biomedical applications. However, there still exists a bottleneck in the compatibility of polymeric biomaterials with different 3D printing methods, as well as intrinsic challenges such as limited printing resolution and rates. Therefore, this review aims to introduce the current state-of-the-art in 3D-printed functional polymeric health-related devices. It begins with an overview of the landscape of 3D printing techniques, followed by an examination of commonly used polymeric biomaterials. Subsequently, examples of 3D-printed biomedical devices are provided and classified into categories such as biosensors, bioactuators, soft robotics, energy storage systems, self-powered devices, and data science in bioplotting. The emphasis is on exploring the current capabilities of 3D printing in manufacturing polymeric biomaterials into desired geometries that facilitate device functionality and studying the reasons for material choice. Finally, an outlook with challenges and possible improvements in the near future is presented, projecting the contribution of general 3D printing and polymeric biomaterials in the field of healthcare.",,,,,Open Access +PublicationView,CA245313,TEC,"Microenvironment, Metastasis, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.cell.2024.09.001,Cell,39353436,https://pubmed.ncbi.nlm.nih.gov/39353436,Spatially exploring RNA biology in archival formalin-fixed paraffin-embedded tissues,2024,"Spatiotemporal dynamics, Histopathology, MicroRNA, Whole Transcriptome, Rna Biology, Splicing Isoforms, Spatial Omics, Clinical Ffpe Tissue, Single-nucleotide Rna Variants","Zhiliang Bai, Dingyao Zhang, Yan Gao, Bo Tao, Daiwei Zhang, Shuozhen Bao, Archibald Enninful, Yadong Wang, Haikuo Li, Graham Su, Xiaolong Tian, Ningning Zhang, Yang Xiao, Yang Liu, Mark Gerstein, Mingyao Li, Yi Xing, Jun Lu, Mina L Xu, Rong Fan","The capability to spatially explore RNA biology in formalin-fixed paraffin-embedded (FFPE) tissues holds transformative potential for histopathology research. Here, we present pathology-compatible deterministic barcoding in tissue (Patho-DBiT) by combining in situ polyadenylation and computational innovation for spatial whole transcriptome sequencing, tailored to probe the diverse RNA species in clinically archived FFPE samples. It permits spatial co-profiling of gene expression and RNA processing, unveiling region-specific splicing isoforms, and high-sensitivity transcriptomic mapping of clinical tumor FFPE tissues stored for 5 years. Furthermore, genome-wide single-nucleotide RNA variants can be captured to distinguish malignant subclones from non-malignant cells in human lymphomas. Patho-DBiT also maps microRNA regulatory networks and RNA splicing dynamics, decoding their roles in spatial tumorigenesis. Single-cell level Patho-DBiT dissects the spatiotemporal cellular dynamics driving tumor clonal architecture and progression. Patho-DBiT stands poised as a valuable platform to unravel rich RNA biology in FFPE tissues to aid in clinical pathology evaluation.",,,,,Open Access +PublicationView,CA224013,PDMC,"Heterogeneity, Microenvironment",https://doi.org/10.1158/2159-8290.cd-23-1529,Cancer Discov,39058094,https://pubmed.ncbi.nlm.nih.gov/39058094,MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer,2024,,"Olaf Klingbeil, Damianos Skopelitis, Claudia Tonelli, Toyoki Yoshimoto, Aktan Alpsoy, Maria C Panepinto, Francesca Minicozzi, Joseph R Merrill, Amanda M Cafiero, Disha Aggarwal, Suzanne Russo, Taehoon Ha, Osama E Demerdash, Tse-Luen Wee, David L Spector, Scott K Lyons, David A Tuveson, Paolo Cifani, Christopher R Vakoc","The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.",,,,"GSE242516, GSE242517, GSE241897",Open Access +PublicationView,CA225088,CSBC,"Microenvironment, Drug Resistance/Sensitivity",https://doi.org/10.1038/s41586-024-08031-6,Nature,39385030,https://pubmed.ncbi.nlm.nih.gov/39385030,AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution,2024,,"Amy E Schade, Naiara Perurena, Yoona Yang, Carrie L Rodriguez, Anjana Krishnan, Alycia Gardner, Patrick Loi, Yilin Xu, Van T M Nguyen, G M Mastellone, Natalie F Pilla, Marina Watanabe, Keiichi Ota, Rachel A Davis, Kaia Mattioli, Dongxi Xiang, Jason J Zoeller, Jia-Ren Lin, Stefania Morganti, Ana C Garrido-Castro, Sara M Tolaney, Zhe Li, David A Barbie, Peter K Sorger, Kristian Helin, Sandro Santagata, Simon R V Knott, Karen Cichowski","Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence1. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived1,2. Thus, there is an urgent need to develop more effective treatments. Components of the PI3K pathway represent plausible therapeutic targets; more than 70% of TNBCs have alterations in PIK3CA, AKT1 or PTEN3-6. However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors7. Here we describe a promising AKT-inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once TNBCs are differentiated, these agents kill them by hijacking signals that normally drive mammary gland involution. Using a machine learning approach, we developed a classifier that can be used to predict sensitivity. Together, these findings identify a promising therapeutic strategy for this highly aggressive tumour type and illustrate how deregulated epigenetic enzymes can insulate tumours from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.",,,,,Open Access +PublicationView,CA217378,CSBC,"Heterogeneity, Evolution, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.neuron.2024.07.018,Neuron,39153478,https://pubmed.ncbi.nlm.nih.gov/39153478,Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity,2024,"Rabies virus, Dopamine, Cocaine, Globus pallidus, Ventral tegmental area, Carnosic acid, Drug abuse, voltage-gated potassium channels, Intrinsic Excitability, Chemogenetics, Behavioral Vulnerability","Guilian Tian, Katrina Bartas, May Hui, Lingxuan Chen, Jose J Vasquez, Ghalia Azouz, Pieter Derdeyn, Rían W Manville, Erick L Ho, Amanda S Fang, Yuan Li, Isabella Tyler, Vincent Setola, Jason Aoto, Geoffrey W Abbott, Kevin T Beier","The globus pallidus externus (GPe) is a central component of the basal ganglia circuit that acts as a gatekeeper of cocaine-induced behavioral plasticity. However, the molecular and circuit mechanisms underlying this function are unknown. Here, we show that GPe parvalbumin-positive (GPePV) cells mediate cocaine responses by selectively modulating ventral tegmental area dopamine (VTADA) cells projecting to the dorsomedial striatum (DMS). Interestingly, GPePV cell activity in cocaine-naive mice is correlated with behavioral responses following cocaine, effectively predicting cocaine sensitivity. Expression of the voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability following cocaine was downregulated, contributing to the elevation in GPePV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPePV cell excitability and impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its therapeutic potential to counteract psychostimulant use disorder.",,,,,Open Access +PublicationView,CA209891,CSBC,"Heterogeneity, Evolution, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.molcel.2024.08.010,Mol Cell,39303722,https://pubmed.ncbi.nlm.nih.gov/39303722,Integrated multi-omics analysis of zinc-finger proteins uncovers roles in RNA regulation,2024,"Zinc finger, RNA binding protein, Rna-seq, Multi-omics, Eclip, Cut&run, Znf277, Slam-seq, Znf473, Ribo-stamp","Maya L Gosztyla, Lijun Zhan, Sara Olson, Xintao Wei, Jack Naritomi, Grady Nguyen, Lena Street, Grant A Goda, Francisco F Cavazos, Jonathan C Schmok, Manya Jain, Easin Uddin Syed, Eunjeong Kwon, Wenhao Jin, Eric Kofman, Alexandra T Tankka, Allison Li, Valerie Gonzalez, Eric Lécuyer, Daniel Dominguez, Marko Jovanovic, Brenton R Graveley, Gene W Yeo","RNA interactome studies have revealed that hundreds of zinc-finger proteins (ZFPs) are candidate RNA-binding proteins (RBPs), yet their RNA substrates and functional significance remain largely uncharacterized. Here, we present a systematic multi-omics analysis of the DNA- and RNA-binding targets and regulatory roles of more than 100 ZFPs representing 37 zinc-finger families. We show that multiple ZFPs are previously unknown regulators of RNA splicing, alternative polyadenylation, stability, or translation. The examined ZFPs show widespread sequence-specific RNA binding and preferentially bind proximal to transcription start sites. Additionally, several ZFPs associate with their targets at both the DNA and RNA levels. We highlight ZNF277, a C2H2 ZFP that binds thousands of RNA targets and acts as a multi-functional RBP. We also show that ZNF473 is a DNA/RNA-associated protein that regulates the expression and splicing of cell cycle genes. Our results reveal diverse roles for ZFPs in transcriptional and post-transcriptional gene regulation.",,,,,Open Access +PublicationView,CA217376,CSBC,"Heterogeneity, Epigenetics, Microenvironment, Evolution",https://doi.org/10.1158/2159-8290.cd-24-0573,Cancer Discov,39445720,https://pubmed.ncbi.nlm.nih.gov/39445720,Cancer Prevalence across Vertebrates,2024,,"Zachary T Compton, Walker Mellon, Valerie K Harris, Shawn Rupp, Diego Mallo, Stefania E Kapsetaki, Mallory Wilmot, Ryan Kennington, Kathleen Noble, Cristina Baciu, Lucia N Ramirez, Ashley Peraza, Brian Martins, Sushil Sudhakar, Selin Aksoy, Gabriela Furukawa, Orsolya Vincze, Mathieu Giraudeau, Elizabeth G Duke, Simon Spiro, Edmund Flach, Hannah Davidson, Christopher I Li, Ashley Zehnder, Trevor A Graham, Brigid V Troan, Tara M Harrison, Marc Tollis, Joshua D Schiffman, C Athena Aktipis, Lisa M Abegglen, Carlo C Maley, Amy M Boddy","Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto's paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes.",,,,,Open Access +PublicationView,"CA274492, CA209975",CSBC,"Immunotherapy, Metastasis, Tumor-Immune, Computational Model Development, Microenvironment, Drug Resistance/Sensitivity",https://doi.org/10.1038/s43018-024-00838-6,Nat Cancer,39394434,https://pubmed.ncbi.nlm.nih.gov/39394434,The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1,2024,,"Rodrigo Romero, Tinyi Chu, Tania J González Robles, Perianne Smith, Yubin Xie, Harmanpreet Kaur, Sara Yoder, Huiyong Zhao, Chenyi Mao, Wenfei Kang, Maria V Pulina, Kayla E Lawrence, Anuradha Gopalan, Samir Zaidi, Kwangmin Yoo, Jungmin Choi, Ning Fan, Olivia Gerstner, Wouter R Karthaus, Elisa DeStanchina, Kelly V Ruggles, Peter M K Westcott, Ronan Chaligné, Dana Pe'er, Charles L Sawyers","Lineage plasticity is a hallmark of cancer progression that impacts therapy outcomes, yet the mechanisms mediating this process remain unclear. Here, we introduce a versatile in vivo platform to interrogate neuroendocrine lineage transformation throughout prostate cancer progression. Transplanted mouse prostate organoids with human-relevant driver mutations (Rb1-/-; Trp53-/-; cMyc+ or Pten-/-; Trp53-/-; cMyc+) develop adenocarcinomas, but only those with Rb1 deletion advance to aggressive, ASCL1+ neuroendocrine prostate cancer (NEPC) resistant to androgen receptor signaling inhibitors. Notably, this transition requires an in vivo microenvironment not replicated by conventional organoid culture. Using multiplexed immunofluorescence and spatial transcriptomics, we reveal that ASCL1+ cells arise from KRT8+ luminal cells, progressing into transcriptionally heterogeneous ASCL1+;KRT8- NEPC. Ascl1 loss in established NEPC causes transient regression followed by recurrence, but its deletion before transplantation abrogates lineage plasticity, resulting in castration-sensitive adenocarcinomas. This dynamic model highlights the importance of therapy timing and offers a platform to identify additional lineage plasticity drivers.",,,,GSE246251,Open Access +PublicationView,CA244100,PS-ON,"Drug Resistance/Sensitivity, Tumor-Immune",https://doi.org/10.1038/s41540-024-00439-0,NPJ Syst Biol Appl,39358360,https://pubmed.ncbi.nlm.nih.gov/39358360,Calibrating tumor growth and invasion parameters with spectral spatial analysis of cancer biopsy tissues,2024,,"Stefano Pasetto, Michael Montejo, Mohammad U Zahid, Marilin Rosa, Robert Gatenby, Pirmin Schlicke, Roberto Diaz, Heiko Enderling","The reaction-diffusion equation is widely used in mathematical models of cancer. The calibration of model parameters based on limited clinical data is critical to using reaction-diffusion equation simulations for reliable predictions on a per-patient basis. Here, we focus on cell-level data as routinely available from tissue biopsies used for clinical cancer diagnosis. We analyze the spatial architecture in biopsy tissues stained with multiplex immunofluorescence. We derive a two-point correlation function and the corresponding spatial power spectral distribution. We show that this data-deduced power spectral distribution can fit the power spectrum of the solution of reaction-diffusion equations that can then identify patient-specific tumor growth and invasion rates. This approach allows the measurement of patient-specific critical tumor dynamical properties from routinely available biopsy material at a single snapshot in time.",,,,,Open Access +PublicationView,CA253553,CSBC,"Metabolism, Tumor-Immune",https://doi.org/10.3390/cancers16203525,Cancers (Basel),39456619,https://pubmed.ncbi.nlm.nih.gov/39456619,Beyond Primary HER2 Expression: Trastuzumab Deruxtecan's Efficacy in Brain Metastasis,2024,,"Glori Das, Stephen T C Wong, Hong Zhao","This commentary focuses on the DESTINY-Breast12 study, published in Nature Medicine on 13 September 2024, which evaluates the efficacy of Trastuzumab deruxtecan (T-DXd) in treating HER2-positive advanced breast cancer, including those with brain metastases. We emphasize the broadened clinical potential of T-DXd in treating brain metastases from tumors originally classified as HER2-null or HER2-low, extending beyond its current use for breast cancer. This expanded application of T-DXd could provide new hope to patients dealing with challenging brain metastases, addressing an urgent need for effective treatment options.",,,,,Open Access +PublicationView,CA232137,CSBC,"Heterogeneity, Microenvironment, Metabolism",https://doi.org/10.1093/bib/bbae509,Brief Bioinform,39425527,https://pubmed.ncbi.nlm.nih.gov/39425527,"Building multiscale models with PhysiBoSS, an agent-based modeling tool",2024,"Agent-based Modeling, Boolean Modeling, Multiscale Modeling","Marco Ruscone, Andrea Checcoli, Randy Heiland, Emmanuel Barillot, Paul Macklin, Laurence Calzone, Vincent Noël","Multiscale models provide a unique tool for analyzing complex processes that study events occurring at different scales across space and time. In the context of biological systems, such models can simulate mechanisms happening at the intracellular level such as signaling, and at the extracellular level where cells communicate and coordinate with other cells. These models aim to understand the impact of genetic or environmental deregulation observed in complex diseases, describe the interplay between a pathological tissue and the immune system, and suggest strategies to revert the diseased phenotypes. The construction of these multiscale models remains a very complex task, including the choice of the components to consider, the level of details of the processes to simulate, or the fitting of the parameters to the data. One additional difficulty is the expert knowledge needed to program these models in languages such as C++ or Python, which may discourage the participation of non-experts. Simplifying this process through structured description formalisms-coupled with a graphical interface-is crucial in making modeling more accessible to the broader scientific community, as well as streamlining the process for advanced users. This article introduces three examples of multiscale models which rely on the framework PhysiBoSS, an add-on of PhysiCell that includes intracellular descriptions as continuous time Boolean models to the agent-based approach. The article demonstrates how to construct these models more easily, relying on PhysiCell Studio, the PhysiCell Graphical User Interface. A step-by-step tutorial is provided as Supplementary Material and all models are provided at https://physiboss.github.io/tutorial/.",,,,,Open Access +PublicationView,CA232216,CSBC,"Heterogeneity, Microenvironment, Tumor-Immune",https://doi.org/10.1038/s41540-024-00447-0,NPJ Syst Biol Appl,39389979,https://pubmed.ncbi.nlm.nih.gov/39389979,Systems profiling reveals recurrently dysregulated cytokine signaling responses in ER+ breast cancer patients' blood,2024,,"Brian Orcutt-Jahns, Joao Rodrigues Lima Junior, Emily Lin, Russell C Rockne, Adina Matache, Sergio Branciamore, Ethan Hung, Andrei S Rodin, Peter P Lee, Aaron S Meyer","Cytokines operate in concert to maintain immune homeostasis and coordinate immune responses. In cases of ER+ breast cancer, peripheral immune cells exhibit altered responses to several cytokines, and these alterations are correlated strongly with patient outcomes. To develop a systems-level understanding of this dysregulation, we measured a panel of cytokine responses and receptor abundances in the peripheral blood of healthy controls and ER+ breast cancer patients across immune cell types. Using tensor factorization to model this multidimensional data, we found that breast cancer patients exhibited widespread alterations in response, including drastically reduced response to IL-10 and heightened basal levels of pSmad2/3 and pSTAT4. ER+ patients also featured upregulation of PD-L1, IL6Rα, and IL2Rα, among other receptors. Despite this, alterations in response to cytokines were not explained by changes in receptor abundances. Thus, tensor factorization helped to reveal a coordinated reprogramming of the immune system that was consistent across our cohort.",,,,,Open Access +PublicationView,"CA210181, CA253553","PS-ON, CSBC","Heterogeneity, Microenvironment, Metabolism, Tumor-Immune",https://doi.org/10.1158/2767-9764.crc-24-0235,Cancer Res Commun,39356141,https://pubmed.ncbi.nlm.nih.gov/39356141,Tumor NOS2 and COX2 Spatial Juxtaposition with CD8+ T Cells Promote Metastatic and Cancer Stem Cell Niches that Lead to Poor Outcome in ER- Breast Cancer,2024,,"Lisa A Ridnour, William F Heinz, Robert Y S Cheng, Adelaide L Wink, Noemi Kedei, Milind Pore, Fatima Imtiaz, Elise L Femino, Ana L Gonzalez, Leandro L Coutinho, Rebecca L Moffat, Donna Butcher, Elijah F Edmondson, Xiaoxian Li, Maria Cristina Rangel, Robert J Kinders, Jens Rittscher, Stanley Lipkowitz, Stephen T C Wong, Stephen K Anderson, Daniel W McVicar, Sharon A Glynn, Timothy R Billiar, Jenny C Chang, Stephen M Hewitt, Stefan Ambs, Stephen J Lockett, David A Wink",Significance: This work identifies CD8-NOS2+COX2+ and CD8-NOS2-COX2+ unique cellular neighborhoods that drive the tumor immune spatial architecture of CD8+ T cells predictive of clinical outcome and can be targeted with clinically available NOS inhibitors and NSAIDs.,,,,,Open Access +PublicationView,CA250481,PS-ON,Tumor-Immune,https://doi.org/10.1038/s41746-024-01277-4,NPJ Digit Med,39427044,https://pubmed.ncbi.nlm.nih.gov/39427044,Biologically informed deep neural networks provide quantitative assessment of intratumoral heterogeneity in post treatment glioblastoma,2024,,"Hairong Wang, Michael G Argenziano, Hyunsoo Yoon, Deborah Boyett, Akshay Save, Petros Petridis, William Savage, Pamela Jackson, Andrea Hawkins-Daarud, Nhan Tran, Leland Hu, Kyle W Singleton, Lisa Paulson, Osama Al Dalahmah, Jeffrey N Bruce, Jack Grinband, Kristin R Swanson, Peter Canoll, Jing Li","Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of recurrent glioblastoma. This study addresses the need for non-invasive approaches to map heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We developed BioNet, a biologically-informed neural network, to predict regional distributions of two primary tissue-specific gene modules: proliferating tumor (Pro) and reactive/inflammatory cells (Inf). BioNet significantly outperforms existing methods (p < 2e-26). In cross-validation, BioNet achieved AUCs of 0.80 (Pro) and 0.81 (Inf), with accuracies of 80% and 75%, respectively. In blind tests, BioNet achieved AUCs of 0.80 (Pro) and 0.76 (Inf), with accuracies of 81% and 74%. Competing methods had AUCs lower or around 0.6 and accuracies lower or around 70%. BioNet's voxel-level prediction maps reveal intratumoral heterogeneity, potentially improving biopsy targeting and treatment evaluation. This non-invasive approach facilitates regular monitoring and timely therapeutic adjustments, highlighting the role of ML in precision medicine.",,,,,Open Access +PublicationView,CA267170,TEC,Microenvironment,https://doi.org/10.1080/21623945.2024.2414919,Adipocyte,39415617,https://pubmed.ncbi.nlm.nih.gov/39415617,An improved <i>in vitro</i> 3T3-L1 adipocyte model of inflammation and insulin resistance,2024,"Inflammation, Insulin resistance, Adipocyte, 3T3-L1 cells, in vitro model","Ifeoluwa A Odeniyi, Bulbul Ahmed, Benjamin Anbiah, Grace Hester, Peter T Abraham, Elizabeth A Lipke, Michael W Greene","Tumor necrosis factor alpha (TNF-α)/hypoxia-treated 3T3-L1 adipocytes have been used to model inflamed and insulin-resistant adipose tissue: this study examines gaps in the model. We tested whether modulating TNF-α/hypoxia treatment time could reduce cell death while still inducing inflammation and insulin resistance. Adipocytes were treated with TNF-α (12 h or 24 h) and incubated in a hypoxic chamber for 24 h. To examine maintenance of the phenotype over time, glucose and FBS were added at 24 h post initiation of treatment, and the cells were maintained for an additional 48 h. Untreated adipocytes were used as a control. Viability, insulin resistance, and inflammation were assessed using Live/Dead staining, RT-qPCR, ELISA, and glucose uptake assays. Treatment for 12 h with TNF-α in the presence of hypoxia resulted in an increase in the percentage of live cells compared to 24 h treated cells. Importantly, insulin resistance and inflammation were still induced in the 12 h treated adipocytes: the expression of the insulin sensitive and inflammatory genes was decreased and increased, respectively. In 72 h treated adipocytes, no significant differences were found in the viability, glucose uptake or insulin-sensitive and inflammatory gene expression. This study provides a modified approach to in vitro odeling adipocyte inflammation and insulin resistance.        .",,,,,Open Access +PublicationView,CA274507,CSBC,"Computational Model Development, Drug Resistance/Sensitivity",https://doi.org/10.1038/s41540-024-00438-1,NPJ Syst Biol Appl,39349537,https://pubmed.ncbi.nlm.nih.gov/39349537,Spatial interactions modulate tumor growth and immune infiltration,2024,,"Sadegh Marzban, Sonal Srivastava, Sharon Kartika, Rafael Bravo, Rachel Safriel, Aidan Zarski, Alexander R A Anderson, Christine H Chung, Antonio L Amelio, Jeffrey West","Direct observation of tumor-immune interactions is unlikely in tumors with currently available technology, but computational simulations based on clinical data can provide insight to test hypotheses. It is hypothesized that patterns of collagen evolve as a mechanism of immune escape, but the exact nature of immune-collagen interactions is poorly understood. Spatial data quantifying collagen fiber alignment in squamous cell carcinomas indicates that late-stage disease is associated with highly aligned fibers. Our computational modeling framework discriminates between two hypotheses: immune cell migration that moves (1) parallel or (2) perpendicular to collagen fiber orientation. The modeling recapitulates immune-extracellular matrix interactions where collagen patterns provide immune protection, leading to an emergent inverse relationship between disease stage and immune coverage. Here, computational modeling provides important mechanistic insights by defining a kernel cell-cell interaction function that considers a spectrum of local (cell-scale) to global (tumor-scale) spatial interactions. Short-range interaction kernels provide a mechanism for tumor cell survival under conditions with strong Allee effects, while asymmetric tumor-immune interaction kernels lead to poor immune response. Thus, the length scale of tumor-immune interaction kernels drives tumor growth and infiltration.",,,,,Open Access +PublicationView,CA228963,PS-ON,Tumor-Immune,https://doi.org/10.1097/hc9.0000000000000533,Hepatol Commun,39330965,https://pubmed.ncbi.nlm.nih.gov/39330965,HCC spatial transcriptomic profiling reveals significant and potentially targetable cancer-endothelial interactions,2024,,"Chenyue Lu, Amaya Pankaj, Michael Raabe, Cole Nawrocki, Ann Liu, Nova Xu, Bidish K Patel, Matthew J Emmett, Avril K Coley, Cristina R Ferrone, Vikram Deshpande, Irun Bhan, Yujin Hoshida, David T Ting, Martin J Aryee, Joseph W Franses","Background: HCC is a highly vascular tumor, and many effective drug regimens target the tumor blood vessels. Prior bulk HCC subtyping data used bulk transcriptomes, which contained a mixture of parenchymal and stromal contributions. Methods: We utilized computational deconvolution and cell-cell interaction analyses to cell type-specific (tumor-enriched and vessel-enriched) spatial transcriptomic data collected from 41 resected HCC tissue specimens. Results: We report that the prior Hoshida bulk transcriptional subtyping schema is driven largely by an endothelial fraction, show an alternative tumor-specific schema has potential prognostic value, and use spatially paired ligand-receptor analyses to identify known and novel (LGALS9 tumor-HAVCR2 vessel) signaling relationships that drive HCC biology in a subtype-specific and potentially targetable manner. Conclusions: Our study leverages spatial gene expression profiling technologies to dissect HCC heterogeneity and identify heterogeneous signaling relationships between cancer cells and their endothelial cells. Future validation and expansion of these findings may validate novel cancer-endothelial cell interactions and related drug targets.",,,,GSE277104,Open Access +PublicationView,CA268069,CCBIR,"Immunotherapy, Microenvironment, Platform Development, Tumor-Immune",https://doi.org/10.1117/1.jbo.29.9.093511,J Biomed Opt,39364328,https://pubmed.ncbi.nlm.nih.gov/39364328,Machine learning-assisted mid-infrared spectrochemical fibrillar collagen imaging in clinical tissues,2024,"Cancer, second harmonic generation, Tumor Microenvironment, Machine Learning, Mid-infrared Spectral Imaging, Fibrillar Collagen Imaging","Wihan Adi, Bryan E Rubio Perez, Yuming Liu, Sydney Runkle, Kevin W Eliceiri, Filiz Yesilkoy","Significance: Label-free multimodal imaging methods that can provide complementary structural and chemical information from the same sample are critical for comprehensive tissue analyses. These methods are specifically needed to study the complex tumor-microenvironment where fibrillar collagen's architectural changes are associated with cancer progression. To address this need, we present a multimodal computational imaging method where mid-infrared spectral imaging (MIRSI) is employed with second harmonic generation (SHG) microscopy to identify fibrillar collagen in biological tissues. Aim: To demonstrate a multimodal approach where a morphology-specific contrast mechanism guides an MIRSI method to detect fibrillar collagen based on its chemical signatures. Approach: We trained a supervised machine learning (ML) model using SHG images as ground truth collagen labels to classify fibrillar collagen in biological tissues based on their mid-infrared hyperspectral images. Five human pancreatic tissue samples (sizes are in the order of millimeters) were imaged by both MIRSI and SHG microscopes. In total, 2.8 million MIRSI spectra were used to train a random forest (RF) model. The other 68 million spectra were used to validate the collagen images generated by the RF-MIRSI model in terms of collagen segmentation, orientation, and alignment. Results: Compared with the SHG ground truth, the generated RF-MIRSI collagen images achieved a high average boundary F -score (0.8 at 4-pixel thresholds) in the collagen distribution, high correlation (Pearson's R 0.82) in the collagen orientation, and similarly high correlation (Pearson's R 0.66) in the collagen alignment. Conclusions: We showed the potential of ML-aided label-free mid-infrared hyperspectral imaging for collagen fiber and tumor microenvironment analysis in tumor pathology samples.",,,,,Open Access +PublicationView,"CA274506, CA249799","TEC, CSBC","Metastasis, Platform Development, Tumor-Immune, Microenvironment, Drug Resistance/Sensitivity",https://doi.org/10.1073/pnas.2405257121,Proc Natl Acad Sci U S A,39374382,https://pubmed.ncbi.nlm.nih.gov/39374382,An engineered model of metastatic colonization of human bone marrow reveals breast cancer cell remodeling of the hematopoietic niche,2024,"Cancer, Tissue engineering, Hematopoiesis, Metastasis, Organoids","Ilaria Baldassarri, Daniel Naveed Tavakol, Pamela L Graney, Alan G Chramiec, Hanina Hibshoosh, Gordana Vunjak-Novakovic","Incomplete understanding of metastatic disease mechanisms continues to hinder effective treatment of cancer. Despite remarkable advancements toward the identification of druggable targets, treatment options for patients in remission following primary tumor resection remain limited. Bioengineered human tissue models of metastatic sites capable of recreating the physiologically relevant milieu of metastatic colonization may strengthen our grasp of cancer progression and contribute to the development of effective therapeutic strategies. We report the use of an engineered tissue model of human bone marrow (eBM) to identify microenvironmental cues regulating cancer cell proliferation and to investigate how triple-negative breast cancer (TNBC) cell lines influence hematopoiesis. Notably, individual stromal components of the bone marrow niche (osteoblasts, endothelial cells, and mesenchymal stem/stromal cells) were each critical for regulating tumor cell quiescence and proliferation in the three-dimensional eBM niche. We found that hematopoietic stem and progenitor cells (HSPCs) impacted TNBC cell growth and responded to cancer cell presence with a shift of HSPCs (CD34+CD38-) to downstream myeloid lineages (CD11b+CD14+). To account for tumor heterogeneity and show proof-of-concept ability for patient-specific studies, we demonstrate that patient-derived tumor organoids survive and proliferate in the eBM, resulting in distinct shifts in myelopoiesis that are similar to those observed for aggressively metastatic cell lines. We envision that this human tissue model will facilitate studies of niche-specific metastatic progression and individualized responses to treatment.",,,,,Open Access +PublicationView,CA214354,PS-ON,"Microenvironment, Tumor-Immune",https://doi.org/10.1039/d4bm00910j,Biomater Sci,39318195,https://pubmed.ncbi.nlm.nih.gov/39318195,Different leukocyte subsets are targeted by systemic and locoregional administration despite conserved nanomaterial characteristics optimal for lymph node delivery,2024,,"Paul A Archer, Alexander J Heiler, Alisyn R Bourque, Yunus Alapan, Susan N Thomas","Lymph nodes (LNs) house a large proportion of the body's leukocytes. Accordingly, engineered nanomaterials are increasingly developed to direct therapeutics to LNs to enhance their efficacy. Yet while lymphatic delivery of nanomaterials to LNs upon locoregional injection has been extensively evaluated, nanomaterial delivery to LN-localized leukocytes after intravenous administration has not been systematically explored nor benchmarked. In this work, a panel of inert, fluorescent nanoscale tracers and drug delivery vehicles were utilized to interrogate intravenous versus locoregionally administered nanomaterial access to LNs and leukocyte subsets therein. Hydrodynamic size and material effects on LN accumulation extents were similar between intravenous versus intradermal injection routes. Nanomaterial distribution to various LN leukocyte subsets differed substantially with injection route, however, in a manner not proportional to total LN accumulation. While intravenously administered nanomaterials accumulated in LNs lowly compared to systemic tissues, in sharp contrast to locoregional delivery, they exhibited size-dependent but material-independent access to immune cells within the LN parenchyma, which are not easily accessed with locoregional delivery.",,,,,Open Access +PublicationView,"CA220378, CA250481","PS-ON, CSBC","Heterogeneity, Evolution, Tumor-Immune",https://doi.org/10.3174/ajnr.a8357,AJNR Am J Neuroradiol,38782593,https://pubmed.ncbi.nlm.nih.gov/38782593,"Identification of a Single-Dose, Low-Flip-Angle-Based CBV Threshold for Fractional Tumor Burden Mapping in Recurrent Glioblastoma",2024,,"Aliya Anil, Ashley M Stokes, John P Karis, Laura C Bell, Jennifer Eschbacher, Kristofer Jennings, Melissa A Prah, Leland S Hu, Jerrold L Boxerman, Kathleen M Schmainda, C Chad Quarles","Background and purpose: DSC-MR imaging can be used to generate fractional tumor burden (FTB) maps via application of relative CBV thresholds to spatially differentiate glioblastoma recurrence from posttreatment radiation effects (PTRE). Image-localized histopathology was previously used to validate FTB maps derived from a reference DSC-MR imaging protocol by using preload, a moderate flip angle (MFA, 60°), and postprocessing leakage correction. Recently, a DSC-MR imaging protocol with a low flip angle (LFA, 30°) with no preload was shown to provide leakage-corrected relative CBV (rCBV) equivalent to the reference protocol. This study aimed to identify the rCBV thresholds for the LFA protocol that generate the most accurate FTB maps, concordant with those obtained from the reference MFA protocol. Materials and methods: Fifty-two patients with grade-IV glioblastoma who had prior surgical resection and received chemotherapy and radiation therapy were included in the study. Two sets of DSC-MR imaging data were collected sequentially first by using LFA protocol with no preload, which served as the preload for the subsequent MFA protocol. Standardized relative CBV maps (sRCBV) were obtained for each patient and coregistered with the anatomic postcontrast T1-weighted images. The reference MFA-based FTB maps were computed by using previously published sRCBV thresholds (1.0 and 1.56). A receiver operating characteristics (ROC) analysis was conducted to identify the optimal, voxelwise LFA sRCBV thresholds, and the sensitivity, specificity, and accuracy of the LFA-based FTB maps were computed with respect to the MFA-based reference. Results: The mean sRCBV values of tumors across patients exhibited strong agreement (concordance correlation coefficient = 0.99) between the 2 protocols. Using the ROC analysis, the optimal lower LFA threshold that accurately distinguishes PTRE from tumor recurrence was found to be 1.0 (sensitivity: 87.77%; specificity: 90.22%), equivalent to the ground truth. To identify aggressive tumor regions, the ROC analysis identified an upper LFA threshold of 1.37 (sensitivity: 90.87%; specificity: 91.10%) for the reference MFA threshold of 1.56. Conclusions: For LFA-based FTB maps, an sRCBV threshold of 1.0 and 1.37 can differentiate PTRE from recurrent tumors. FTB maps aid in surgical planning, guiding pathologic diagnosis and treatment strategies in the recurrent setting. This study further confirms the reliability of single-dose LFA-based DSC-MR imaging.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA256481,TEC,"Metastasis, Drug Resistance/Sensitivity, Platform Development",https://doi.org/10.1126/scitranslmed.adj5962,Sci Transl Med,38354228,https://pubmed.ncbi.nlm.nih.gov/38354228,Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization,2024,,"Jiajia Chen, Daniel J Laverty, Surabhi Talele, Ashwin Bale, Brett L Carlson, Kendra A Porath, Katrina K Bakken, Danielle M Burgenske, Paul A Decker, Rachael A Vaubel, Jeanette E Eckel-Passow, Rohit Bhargava, Zhenkun Lou, Petra Hamerlik, Brendan Harley, William F Elmquist, Zachary D Nagel, Shiv K Gupta, Jann N Sarkaria","ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G0-G1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53-mutant tumors but not in TP53-WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53-mutant, but not in TP53-WT, PDXs. In plasmid-based reporter assays, GBM43 (TP53-mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53 (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53-mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53-mutant cells to ATM inhibitor-mediated radiosensitization.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA209992,CSBC,"Microenvironment, Metastasis",https://doi.org/10.1016/j.molcel.2024.07.025,Mol Cell,39153475,https://pubmed.ncbi.nlm.nih.gov/39153475,Nuclear PKM2 binds pre-mRNA at folded G-quadruplexes and reveals their gene regulatory role,2024,"RNA-binding proteins, G-quadruplex, Pkm2, G4, Par-clip, Posttranscriptional Gene Regulation, Crosslinking And Immunoprecipitation","Dimitrios G Anastasakis, Maria Apostolidi, Khalid A Garman, Ahsan H Polash, Mubarak I Umar, Qingcai Meng, Jérémy Scutenaire, Jordan E Jarvis, Xiantao Wang, Astrid D Haase, Isaac Brownell, Jesse Rinehart, Markus Hafner","Nuclear localization of the metabolic enzyme PKM2 is widely observed in various cancer types. We identify nuclear PKM2 as a non-canonical RNA-binding protein (RBP) that specifically interacts with folded RNA G-quadruplex (rG4) structures in precursor mRNAs (pre-mRNAs). PKM2 occupancy at rG4s prevents the binding of repressive RBPs, such as HNRNPF, and promotes the expression of rG4-containing pre-mRNAs (the ""rG4ome""). We observe an upregulation of the rG4ome during epithelial-to-mesenchymal transition and a negative correlation of rG4 abundance with patient survival in different cancer types. By preventing the nuclear accumulation of PKM2, we could repress the rG4ome in triple-negative breast cancer cells and reduce migration and invasion of cancer cells in vitro and in xenograft mouse models. Our data suggest that the balance of folded and unfolded rG4s controlled by RBPs impacts gene expression during tumor progression.",Pending Annotation,Pending Annotation,Pending Annotation,GSE179817,Restricted Access +PublicationView,CA227136,TEC,"Microenvironment, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.ccell.2024.08.008,Cancer Cell,39255776,https://pubmed.ncbi.nlm.nih.gov/39255776,"Glioblastoma induces the recruitment and differentiation of dendritic-like ""hybrid"" neutrophils from skull bone marrow",2024,"T cells, Dendritic cells, Myeloid, Glioblastoma, Antigen-presenting cells, Mhc Class Ii, Tumor-associated Neutrophil, Skull Marrow","Meeki Lad, Angad S Beniwal, Saket Jain, Poojan Shukla, Venina Kalistratova, Jangham Jung, Sumedh S Shah, Garima Yagnik, Atul Saha, Ankita Sati, Husam Babikir, Alan T Nguyen, Sabraj Gill, Jennifer Rios, Jacob S Young, Austin Lui, Diana Salha, Aaron Diaz, Manish K Aghi","Tumor-associated neutrophil (TAN) effects on glioblastoma (GBM) biology remain under-characterized. We show here that neutrophils with dendritic features-including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate major histocompatibility complex (MHC)II-dependent T cell activation-accumulate intratumorally and suppress tumor growth in vivo. Trajectory analysis of patient TAN scRNA-seq identifies this ""hybrid"" dendritic-neutrophil phenotype as a polarization state that is distinct from canonical cytotoxic TANs, and which differentiates from local precursors. These hybrid-inducible immature neutrophils-which we identified in patient and murine glioblastomas-arise not from circulation, but from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a contributor of antitumoral myeloid antigen-presenting cells (APCs), including TANs, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow-such as intracalvarial AMD3100, whose survival-prolonging effect in GBM we report-present therapeutic potential.",Pending Annotation,Pending Annotation,Pending Annotation,GSE271618,Restricted Access +PublicationView,CA210180,PS-ON,"Heterogeneity, Microenvironment, Evolution",https://doi.org/10.1158/1078-0432.ccr-24-1849,Clin Cancer Res,39499201,https://pubmed.ncbi.nlm.nih.gov/39499201,Pilot Trial of Perampanel on Peritumoral Hyperexcitability in Newly Diagnosed High-grade Glioma. ,2024,,"Steven Tobochnik, Michael S Regan, Maria K C Dorotan, Dustine Reich, Emily Lapinskas, Md Amin Hossain, Sylwia Stopka, David M Meredith, Sandro Santagata, Melissa M Murphy, Omar Arnaout, Wenya Linda Bi, E Antonio Chiocca, Alexandra J Golby, Michael A Mooney, Timothy R Smith, Keith L Ligon, Patrick Y Wen, Nathalie Y R Agar, Jong Woo Lee","Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the targeted AMPA receptor antagonist perampanel on peritumoral hyperexcitability. An open-label trial was performed comparing perampanel with standard of care (SOC) in patients undergoing resection of newly diagnosed radiologic high-grade glioma. Perampanel was administered as a preoperative loading dose followed by maintenance therapy until progressive disease or up to 12 months. SOC treatment involved levetiracetam for 7 days or as clinically indicated. The primary outcome of hyperexcitability was defined by intraoperative electrocorticography high-frequency oscillation (HFO) rates. Seizure freedom and overall survival were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and correlative biomarkers were measured by mass spectrometry. HFO rates were similar between patients treated with perampanel and levetiracetam. The trial was terminated early after a planned interim analysis, and outcomes assessed in 11 patients (seven perampanel treated; four treated with SOC). Over a median 281 days of postenrollment follow-up, 27% of patients had seizures, including 14% maintained on perampanel and 50% treated with SOC. Overall survival in perampanel-treated patients was similar to that in a glioblastoma reference cohort. Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations. Glioma peritumoral glutamate concentrations correlated with high-gamma oscillation rates. Targeting glutamatergic activity with perampanel achieved similar electrocorticographic hyperexcitability levels as in levetiracetam-treated patients.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,"CA283114, CA238720",CSBC,"Computational Model Development, Drug Resistance/Sensitivity, Tumor-Immune",https://doi.org/10.1038/s41596-024-01076-x,Nat Protoc,39438697,https://pubmed.ncbi.nlm.nih.gov/39438697,Validation and quantification of peptide antigens presented on MHCs using SureQuant,2024,,"Owen Leddy, Yufei Cui, Ryuhjin Ahn, Lauren Stopfer, Elizabeth Choe, Do Hun Kim, Malte Roerden, Stefani Spranger, Bryan D Bryson, Forest M White","Vaccines and immunotherapies that target peptide-major histocompatibility complexes (peptide-MHCs) have the potential to address multiple unmet medical needs in cancer and infectious disease. Designing vaccines and immunotherapies to target peptide-MHCs requires accurate identification of target peptides in infected or cancerous cells or tissue, and may require absolute or relative quantification to identify abundant targets and measure changes in presentation under different treatment conditions. Internal standard parallel reaction monitoring (also known as 'SureQuant') can be used to validate and/or quantify MHC peptides previously identified by using untargeted methods such as data-dependent acquisition. SureQuant MHC has three main use cases: (i) conclusive confirmation of the identities of putative MHC peptides via comparison with an internal synthetic stable isotope labeled (SIL) peptide standard; (ii) accurate relative quantification by using pre-formed heavy isotope-labeled peptide-MHC complexes (hipMHCs) containing SIL peptides as internal controls for technical variation; and (iii) absolute quantification of each target peptide by using different amounts of hipMHCs loaded with synthetic peptides containing one, two or three SIL amino acids to provide an internal standard curve. Absolute quantification can help determine whether the abundance of a peptide-MHC is sufficient for certain therapeutic modalities. SureQuant MHC therefore provides unique advantages for immunologists seeking to confidently validate antigenic targets and understand the dynamics of the MHC repertoire. After synthetic standards are ordered (3-4 weeks), this protocol can be carried out in 3-4 days and is suitable for individuals with mass spectrometry experience who are comfortable with customizing instrument methods.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA261842,PS-ON,Drug Resistance/Sensitivity,https://doi.org/10.1007/s11538-024-01371-4,Bull Math Biol,39460828,https://pubmed.ncbi.nlm.nih.gov/39460828,"AMBER: A Modular Model for Tumor Growth, Vasculature and Radiation Response",2024,"Radiation Response, Agent-based Models, Hybrid Models, Tumor Modeling, Tumor Vascular Modeling","Louis V Kunz, Jesús J Bosque, Mohammad Nikmaneshi, Ibrahim Chamseddine, Lance L Munn, Jan Schuemann, Harald Paganetti, Alejandro Bertolet","Computational models of tumor growth are valuable for simulating the dynamics of cancer progression and treatment responses. In particular, agent-based models (ABMs) tracking individual agents and their interactions are useful for their flexibility and ability to model complex behaviors. However, ABMs have often been confined to small domains or, when scaled up, have neglected crucial aspects like vasculature. Additionally, the integration into tumor ABMs of precise radiation dose calculations using gold-standard Monte Carlo (MC) methods, crucial in contemporary radiotherapy, has been lacking. Here, we introduce AMBER, an Agent-based fraMework for radioBiological Effects in Radiotherapy that computationally models tumor growth and radiation responses. AMBER is based on a voxelized geometry, enabling realistic simulations at relevant pre-clinical scales by tracking temporally discrete states stepwise. Its hybrid approach, combining traditional ABM techniques with continuous spatiotemporal fields of key microenvironmental factors such as oxygen and vascular endothelial growth factor, facilitates the generation of realistic tortuous vascular trees. Moreover, AMBER is integrated with TOPAS, an MC-based particle transport algorithm that simulates heterogeneous radiation doses. The impact of radiation on tumor dynamics considers the microenvironmental factors that alter radiosensitivity, such as oxygen availability, providing a full coupling between the biological and physical aspects. Our results show that simulations with AMBER yield accurate tumor evolution and radiation treatment outcomes, consistent with established volumetric growth laws and radiobiological understanding. Thus, AMBER emerges as a promising tool for replicating essential features of tumor growth and radiation response, offering a modular design for future expansions to incorporate specific biological traits.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,"CA224012, CA209988","PDMC, CSBC","Heterogeneity, Microenvironment, Drug Resistance/Sensitivity, Experimental Model Development",https://doi.org/10.1002/path.6356,J Pathol,39435649,https://pubmed.ncbi.nlm.nih.gov/39435649,Suppression of dystroglycan function accompanies pancreatic acinar-to-ductal metaplasia and favours dysplasia development,2024,"Extracellular matrix, Basement membrane, Dysplasia, Precancer","Ge Huang, Luke Ternes, Christian Lanciault, Kevin MacPherson-Hawthorne, Young Hwan Chang, Rosalie C Sears, John L Muschler","The basement membrane (BM) is among the predominant microenvironmental factors of normal epithelia and of precancerous epithelial lesions. Evidence suggests that the BM functions not only as a barrier to tumour invasion but also as an active tumour-suppressing signalling substrate during premalignancy. However, the molecular foundations of such mechanisms have not been elucidated. Here we explore potential tumour-suppressing functions of the BM during precancer evolution, focusing on the expression and function of the extracellular matrix receptor dystroglycan in the pancreas and pancreatic disease. We show that the dystroglycan protein is highly expressed in the acinar compartment of the normal pancreas but lower in the ductal compartment. Moreover, there is a strong suppression of dystroglycan protein expression with acinar-to-ductal metaplasia in chronic pancreatitis and in all stages of pancreatic precancer and cancer evolution, from acinar-to-ductal metaplasia to dysplasia to adenocarcinoma. The conditional knockout of dystroglycan in the murine pancreas produced little evidence of developmental or functional deficiency. However, conditional deletion of dystroglycan expression in the context of oncogenic Kras expression led to a clear acceleration of pancreatic disease evolution, including accelerated dysplasia development and decreased survival. These data establish dystroglycan as a suppressor of pancreatic dysplasia development and one that is muted in chronic pancreatitis and at the earliest stages of oncogene-induced transformation. We conclude that dystroglycan is an important mediator of the tumour-suppressing functions of the BM during precancer evolution and that reduced dystroglycan function increases cancer risk, highlighting the dynamics of cell-BM interactions as important determinants of early cancer progression. © 2024 The Pathological Society of Great Britain and Ireland.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA244100,PS-ON,"Drug Resistance/Sensitivity, Tumor-Immune",https://doi.org/10.1007/s11538-024-01361-6,Bull Math Biol,39384633,https://pubmed.ncbi.nlm.nih.gov/39384633,Harnessing Flex Point Symmetry to Estimate Logistic Tumor Population Growth,2024,"Logistic function, Tumor Growth, Mathematical Oncology, Evolution Forecasting, Ghost Symmetry","Stefano Pasetto, Isha Harshe, Renee Brady-Nicholls, Robert A Gatenby, Heiko Enderling","The observed time evolution of a population is well approximated by a logistic growth function in many research fields, including oncology, ecology, chemistry, demography, economy, linguistics, and artificial neural networks. Initial growth is exponential, then decelerates as the population approaches its limit size, i.e., the carrying capacity. In mathematical oncology, the tumor carrying capacity has been postulated to be dynamically evolving as the tumor overcomes several evolutionary bottlenecks and, thus, to be patient specific. As the relative tumor-over-carrying capacity ratio may be predictive and prognostic for tumor growth and treatment response dynamics, it is paramount to estimate it from limited clinical data. We show that exploiting the logistic function's rotation symmetry can help estimate the population's growth rate and carry capacity from fewer data points than conventional regression approaches. We test this novel approach against published pan-cancer animal and human breast cancer data, achieving a 30% to 40% reduction in the time at which subsequent data collection is necessary to estimate the logistic growth rate and carrying capacity correctly. These results could improve tumor dynamics forecasting and augment the clinical decision-making process.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA274502,CSBC,"Heterogeneity, Computational Resource",https://doi.org/10.1080/14737140.2024.2417038,Expert Rev Anticancer Ther,39412140,https://pubmed.ncbi.nlm.nih.gov/39412140,Future investigative directions for novel therapeutic targets in head and neck cancer,2024,"Immunotherapy, Radiation Therapy, Pi3k Inhibitors, Hnscc, Breakthough Designation","Jacqueline P Nguyen, Liam C Woerner, Daniel E Johnson, Jennifer R Grandis","Areas covered: Here we describe novel agents, their mechanism(s) of action, preclinical results, and ongoing clinical trials in HNSCC. Expert opinion: Established therapeutic targets in HNSCC include EGFR (cetuximab) and PD-1 (pembrolizumab and nivolumab). Despite the detection of many other possible targets in HNSCC cell lines and patient tumors, no other therapies have successfully advanced to date. Identification of predictive biomarkers may guide the use of targeted agents and combination therapies. Clinical trials supported by strong preclinical data in relevant models are more likely to advance treatment options.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA224012,PDMC,"Heterogeneity, Drug Resistance/Sensitivity, Experimental Model Development",https://doi.org/10.1038/s41388-024-03196-w,Oncogene,39443726,https://pubmed.ncbi.nlm.nih.gov/39443726,KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development,2024,,"Samantha L Tinsley, Ella Rose D Chianis, Rebecca A Shelley, Gaganpreet K Mall, Alisha Dhiman, Garima Baral, Harish Kothandaraman, Mary C Thoma, Isabel A English, Colin J Daniel, Luis Carlos Sanjuan Acosta, Luis Solorio, Nadia Atallah Lanman, Marina Pasca di Magliano, Goutham Narla, Emily C Dykhuizen, Rosalie C Sears, Brittany L Allen-Petersen","Oncogenic mutations in KRAS are present in ~95% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are considered the initiating event of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. While it is well established that KRAS mutations drive the activation of oncogenic kinase cascades during pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (PP2A) has been implicated in suppressing KRAS-driven cellular transformation and low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRASG12D induces the expression of an endogenous inhibitor of PP2A activity, Cancerous Inhibitor of PP2A (CIP2A), and phosphorylation of the PP2A substrate, c-MYC. Consistent with these findings, KRASG12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56α, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation in vivo, knockout of B56α promoted KRASG12D tumorigenesis by accelerating acinar-to-ductal metaplasia (ADM) and the formation of PanIN lesions. The process of ADM was attenuated ex vivo in response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (SMAPs). Together, our results suggest that suppression of PP2A-B56α through KRAS signaling can promote the MYC-driven initiation of pancreatic tumorigenesis.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA274509,CSBC,"Immunotherapy, Computational Model Development",https://doi.org/10.1016/j.cell.2024.08.001,Cell,39181133,https://pubmed.ncbi.nlm.nih.gov/39181133,The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer drug resistance,2024,"DNA repair, DNA replication, Mitosis, Fragile sites, Genomic instability, micronuclei, Genome rearrangements, Fanconi Anemia, Chromothripsis, Ecdna","Justin L Engel, Xiao Zhang, Mingming Wu, Yan Wang, Jose Espejo Valle-Inclán, Qing Hu, Kidist S Woldehawariat, Mathijs A Sanders, Agata Smogorzewska, Jin Chen, Isidro Cortés-Ciriano, Roger S Lo, Peter Ly","Chromothripsis describes the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei. Although micronuclei accumulate DNA double-strand breaks and replication defects throughout interphase, how chromosomes undergo shattering remains unresolved. Using CRISPR-Cas9 screens, we identify a non-canonical role of the Fanconi anemia (FA) pathway as a driver of chromothripsis. Inactivation of the FA pathway suppresses chromosome shattering during mitosis without impacting interphase-associated defects within micronuclei. Mono-ubiquitination of FANCI-FANCD2 by the FA core complex promotes its mitotic engagement with under-replicated micronuclear chromosomes. The structure-selective SLX4-XPF-ERCC1 endonuclease subsequently induces large-scale nucleolytic cleavage of persistent DNA replication intermediates, which stimulates POLD3-dependent mitotic DNA synthesis to prime shattered fragments for reassembly in the ensuing cell cycle. Notably, FA-pathway-induced chromothripsis generates complex genomic rearrangements and extrachromosomal DNA that confer acquired resistance to anti-cancer therapies. Our findings demonstrate how pathological activation of a central DNA repair mechanism paradoxically triggers cancer genome evolution through chromothripsis.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA228963,PS-ON,Tumor-Immune,https://doi.org/10.1016/j.cell.2024.09.024,Cell,39383862,https://pubmed.ncbi.nlm.nih.gov/39383862,Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer,2024,"Pancreatic cancer, Tumor Microenvironment, Extracellular Vesicles, Cellular Plasticity, Cancer-associated Fibroblast, Spatial Transcriptomics, Repeat Rna","Eunae You, Patrick Danaher, Chenyue Lu, Siyu Sun, Luli Zou, Ildiko E Phillips, Alexandra S Rojas, Natalie I Ho, Yuhui Song, Michael J Raabe, Katherine H Xu, Peter M Richieri, Hao Li, Natalie Aston, Rebecca L Porter, Bidish K Patel, Linda T Nieman, Nathan Schurman, Briana M Hudson, Khrystyna North, Sarah E Church, Vikram Deshpande, Andrew S Liss, Tae K Kim, Yi Cui, Youngmi Kim, Benjamin D Greenbaum, Martin J Aryee, David T Ting","Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA227550,CSBC,"Heterogeneity, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.cell.2024.08.013,Cell,39243764,https://pubmed.ncbi.nlm.nih.gov/39243764,Sex-dependent effects in the aged melanoma tumor microenvironment influence invasion and resistance to targeted therapy,2024,"Fibroblast, Melanoma, Aging, DNA damage, Senescence, Metastasis, Epigenetics, sex dimorphism, Tumor Microenvironment, Therapy Resistance, Sex Disparity","Yash Chhabra, Mitchell E Fane, Sneha Pramod, Laura Hüser, Daniel J Zabransky, Vania Wang, Agrani Dixit, Ruzhang Zhao, Edwin Kumah, Megan L Brezka, Kevin Truskowski, Asmita Nandi, Gloria E Marino-Bravante, Alexis E Carey, Naina Gour, Devon A Maranto, Murilo R Rocha, Elizabeth I Harper, Justin Ruiz, Evan J Lipson, Elizabeth M Jaffee, Kristin Bibee, Joel C Sunshine, Hongkai Ji, Ashani T Weeraratna","There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear. While biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Here, we show that skin fibroblasts undergo age-mediated, sex-dependent changes in their proliferation, senescence, ROS levels, and stress response. We find that aged male fibroblasts selectively drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Intrinsic aging in male fibroblasts mediated by EZH2 decline increases BMP2 secretion, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotypes and sensitizes melanoma cells to BRAF/MEK inhibition.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access diff --git a/annotations/oct_filepaths.csv b/annotations/oct_filepaths.csv new file mode 100644 index 00000000..cbfa80b8 --- /dev/null +++ b/annotations/oct_filepaths.csv @@ -0,0 +1,50 @@ +File Paths,folderIdPublication +./output/output_oct/CA210184_publication.csv,syn32698226 +./output/output_oct/CA284090_publication.csv,syn53212987 +./output/output_oct/CA274499_publication.csv,syn43447156 +./output/output_oct/CA210173_publication.csv,syn32698222 +./output/output_oct/CA251443_publication.csv,syn35270499 +./output/output_oct/CA263001_publication.csv,syn43447092 +./output/output_oct/CA217514_publication.csv,syn35270557 +./output/output_oct/CA214297_publication.csv,syn32698320 +./output/output_oct/CA268072_publication.csv,syn35270530 +./output/output_oct/CA224013_publication.csv,syn35270551 +./output/output_oct/CA274502_publication.csv,syn43447174 +./output/output_oct/CA209975_publication.csv,syn32698159 +./output/output_oct/CA217376_publication.csv,syn32698091 +./output/output_oct/CA217378_publication.csv,syn32698086 +./output/output_oct/CA253540_publication.csv,syn32698462 +./output/output_oct/CA224012_publication.csv,syn35270567 +./output/output_oct/CA214354_publication.csv,syn32698033 +./output/output_oct/CA202177_publication.csv,syn32698236 +./output/output_oct/CA217377_publication.csv,syn32698266 +./output/output_oct/CA268084_publication.csv,syn52499923 +./output/output_oct/CA268083_publication.csv,syn35270525 +./output/output_oct/CA250040_publication.csv,syn32698315 +./output/output_oct/CA209992_publication.csv,syn32698178 +./output/output_oct/CA243075_publication.csv,syn32698431 +./output/output_oct/CA232137_publication.csv,syn32698071 +./output/output_oct/CA280849_publication.csv,syn53212962 +./output/output_oct/CA227550_publication.csv,syn32698064 +./output/output_oct/CA209971_publication.csv,syn32698166 +./output/output_oct/CA274506_publication.csv,syn32698150 +./output/output_oct/CA199315_publication.csv,syn32698278 +./output/output_oct/CA253553_publication.csv,syn32698451 +./output/output_oct/CA217450_publication.csv,syn32698096 +./output/output_oct/CA214300_publication.csv,syn32698367 +./output/output_oct/CA231978_publication.csv,syn32698100 +./output/output_oct/CA202123_publication.csv,syn32698231 +./output/output_oct/CA225088_publication.csv,syn32698012 +./output/output_oct/CA261694_publication.csv,syn35270536 +./output/output_oct/CA225566_publication.csv,syn32698345 +./output/output_oct/CA209988_publication.csv,syn32698270 +./output/output_oct/CA232517_publication.csv,syn32698413 +./output/output_oct/CA274511_publication.csv,syn53212942 +./output/output_oct/CA244100_publication.csv,syn32698334 +./output/output_oct/CA282451_publication.csv,syn53212972 +./output/output_oct/CA209891_publication.csv,syn32698008 +./output/output_oct/CA238720_publication.csv,syn32698104 +./output/output_oct/CA244107_publication.csv,syn32698325 +./output/output_oct/CA210152_publication.csv,syn32698024 +./output/output_oct/CA241927_publication.csv,syn32698394 +./output/output_oct/CA210181_publication.csv,syn32698212 diff --git a/annotations/oct_manifest.csv b/annotations/oct_manifest.csv new file mode 100755 index 00000000..6e8b0831 --- /dev/null +++ b/annotations/oct_manifest.csv @@ -0,0 +1,58 @@ +Component,Publication Grant Number,Publication Consortium Name,Publication Theme Name,Publication Doi,Publication Journal,Pubmed Id,Pubmed Url,Publication Title,Publication Year,Publication Keywords,Publication Authors,Publication Abstract,Publication Assay,Publication Tumor Type,Publication Tissue,Publication Dataset Alias,Publication Accessibility +PublicationView,CA274499,CSBC,"Oncogenic Stress, Metabolism",10.1016/j.celrep.2024.114775,Cell Rep,39305483,https://pubmed.ncbi.nlm.nih.gov/39305483,Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations,2024,"Oxidative phosphorylation, Glioma, PTEN, Mitochondrial electron transport chain, Multivariate Modeling, Synthetic Lethality, Cancer Metabolism, Cancer Therapies, Cp: Cancer, Cp: Metabolism, Metabolic State Vulnerabilities","Cara Abecunas, Audrey D Kidd, Ying Jiang, Hui Zong, Mohammad Fallahi-Sichani","Targeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges to identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tumor lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings via analysis of data from patient-derived tumors and pharmacological screens and by performing genetic and pharmacological experiments. Our analysis uncovers synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating the mechanisms underlying these relationships can inform the development of more precise and context-specific, metabolism-targeted cancer therapies.","Western Blotting, RNA Sequencing, Cell Culture",Pan-Cancer,Not Applicable,,Open Access +PublicationView,CA231978,CSBC,"Heterogeneity, Drug Resistance/Sensitivity",10.1016/j.coisb.2019.09.003,Curr Opin Syst Biol,37736115,https://pubmed.ncbi.nlm.nih.gov/37736115,Modeling genetic heterogeneity of drug response and resistance in cancer,2019,,"Teemu D Laajala, Travis Gerke, Svitlana Tyekucheva, James C Costello","Heterogeneity in tumors is recognized as a key contributor to drug resistance and spread of advanced disease, but deep characterization of genetic variation within tumors has only recently been quantifiable with the advancement of next generation sequencing and single cell technologies. These data have been essential in developing molecular models of how tumors develop, evolve, and respond to environmental changes, such as therapeutic intervention. A deeper understanding of tumor evolution has subsequently opened up new research efforts to develop mathematical models that account for evolutionary dynamics with the goal of predicting drug response and resistance in cancer. Here, we describe recent advances and limitations of how models of tumor evolution can impact treatment strategies for cancer patients.",,,,,Open Access +PublicationView,CA232517,TEC,"Microenvironment, Metastasis",10.1126/sciadv.adl4463,Sci Adv,38669327,https://pubmed.ncbi.nlm.nih.gov/38669327,The role of Piezo1 mechanotransduction in high-grade serous ovarian cancer: Insights from an in vitro model of collective detachment,2024,,"Hannah M Micek, Ning Yang, Mayuri Dutta, Lauren Rosenstock, Yicheng Ma, Caitlin Hielsberg, Molly McCord, Jacob Notbohm, Stephanie McGregor, Pamela K Kreeger","Slowing peritoneal spread in high-grade serous ovarian cancer (HGSOC) would improve patient prognosis and quality of life. HGSOC spreads when single cells and spheroids detach, float through the peritoneal fluid and take over new sites, with spheroids thought to be more aggressive than single cells. Using our in vitro model of spheroid collective detachment, we determine that increased substrate stiffness led to the detachment of more spheroids. We identified a mechanism where Piezo1 activity increased MMP-1/MMP-10, decreased collagen I and fibronectin, and increased spheroid detachment. Piezo1 expression was confirmed in omental masses from patients with stage III/IV HGSOC. Using OV90 and CRISPR-modified PIEZO1-/- OV90 in a mouse xenograft model, we determined that while both genotypes efficiently took over the omentum, loss of Piezo1 significantly decreased ascitic volume, tumor spheroids in the ascites, and the number of macroscopic tumors in the mesentery. These results support that slowing collective detachment may benefit patients and identify Piezo1 as a potential therapeutic target.",,,,,Open Access +PublicationView,CA232517,TEC,"Microenvironment, Metastasis",10.3390/cancers16081560,Cancers (Basel),38672642,https://pubmed.ncbi.nlm.nih.gov/38672642,A Perspective Review: Analyzing Collagen Alterations in Ovarian Cancer by High-Resolution Optical Microscopy,2024,"Clinical interventions, High-grade Serous Ovarian Cancer, Collagen Reorganization, Ecm Alterations","Kristal L Gant, Manish S Patankar, Paul J Campagnola","High-grade serous ovarian cancer (HGSOC) is the predominant subtype of ovarian cancer (OC), occurring in more than 80% of patients diagnosed with this malignancy. Histological and genetic analysis have confirmed the secretory epithelial of the fallopian tube (FT) as a major site of origin of HGSOC. Although there have been significant strides in our understanding of this disease, early stage detection and diagnosis are still rare. Current clinical imaging modalities lack the ability to detect early stage pathogenesis in the fallopian tubes and the ovaries. However, there are several microscopic imaging techniques used to analyze the structural modifications in the extracellular matrix (ECM) protein collagen in ex vivo FT and ovarian tissues that potentially can be modified to fit the clinical setting. In this perspective, we evaluate and compare the myriad of optical tools available to visualize these alterations and the invaluable insights these data provide on HGSOC initiation. We also discuss the clinical implications of these findings and how these data may help novel tools for early diagnosis of HGSOC.",,,,,Open Access +PublicationView,"CA253553, CA210181","PS-ON, CSBC","Microenvironment, Heterogeneity, Tumor-Immune, Metabolism",10.1172/jci.insight.165356,JCI Insight,38912586,https://pubmed.ncbi.nlm.nih.gov/38912586,Adjuvant COX inhibition augments STING signaling and cytolytic T cell infiltration in irradiated 4T1 tumors,2024,"Breast cancer, Inflammation, Oncology, adaptive immunity","Lisa A Ridnour, Robert Ys Cheng, Noemi Kedei, Veena Somasundaram, Dibyangana D Bhattacharyya, Debashree Basudhar, Adelaide L Wink, Abigail J Walke, Caleb Kim, William F Heinz, Elijah F Edmondson, Donna O Butcher, Andrew C Warner, Tiffany H Dorsey, Milind Pore, Robert J Kinders, Stanley Lipkowitz, Richard J Bryant, Jens Rittscher, Stephen Tc Wong, Stephen M Hewitt, Jenny C Chang, Aliaa Shalaby, Grace M Callagy, Sharon A Glynn, Stefan Ambs, Stephen K Anderson, Daniel W McVicar, Stephen J Lockett, David A Wink","Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts ""immune desert phenotypes"" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.",,,,"SRX24350068, SRX24350051, SRX24350113, SRX24350088, SRX24350086, SRX24350122, SRX24350126, SRX24350140, SRX24350120, SRX24350077, SRX24350142, SRX24350075, SRX24350134, SRX24350111, SRX24350117, SRX24350101, SRX24350066, SRX24350110, SRX24350136, SRX24350107, SRX24350062, SRX24350132, SRX24350090, SRX24350104, SRX24350095, SRX24350082, SRX24350093, SRX24350084, SRX24350124, SRX24350053, SRX24350102, SRX24350144, SRX24350108, SRX24350099, SRX24350070, SRX24350060, SRX24350098, SRX24350112, SRX24350054, SRX24350130, SRX24350116, SRX24350092, SRX24350071, SRX24350143, SRX24350097, SRX24350118, SRX24350121, SRX24350128, SRX24350129, SRX24350115, SRX24350056, SRX24350061, SRX24350057, SRX24350079, SRX24350067, SRX24350083, SRX24350100, SRX24350094, SRX24350125, SRX24350133, SRX24350105, SRX24350127, SRX24350089, SRX24350063, SRX24350138, SRP503680, SRX24350135, SRX24350114, SRX24350137, SRX24350131, SRX24350069, SRX24350123, SRX24350091, SRX24350109, SRX24350081, SRX24350085, SRX24350139, SRX24350080, SRX24350119, SRX24350058, SRX24350087, SRX24350076, SRX24350055, SRX24350103, SRX24350052, SRX24350059, SRX24350072, SRX24350073, SRX24350141, SRX24350074, SRX24350065, SRX24350078, SRX24350096, GSE264712, SRX24350106, SRX24350064",Open Access +PublicationView,CA199315,ICBP,"Microenvironment, Heterogeneity",10.1172/jci164227,J Clin Invest,39225101,https://pubmed.ncbi.nlm.nih.gov/39225101,Single-cell analysis of breast cancer metastasis reveals epithelial-mesenchymal plasticity signatures associated with poor outcomes,2024,"Breast cancer, Bioinformatics, Oncology","Juliane Winkler, Weilun Tan, Catherine Mm Diadhiou, Christopher S McGinnis, Aamna Abbasi, Saad Hasnain, Sophia Durney, Elena Atamaniuc, Daphne Superville, Leena Awni, Joyce V Lee, Johanna H Hinrichs, Patrick S Wagner, Namrata Singh, Marco Y Hein, Michael Borja, Angela M Detweiler, Su-Yang Liu, Ankitha Nanjaraj, Vaishnavi Sitarama, Hope S Rugo, Norma Neff, Zev J Gartner, Angela Oliveira Pisco, Andrei Goga, Spyros Darmanis, Zena Werb","Metastasis is the leading cause of cancer-related deaths. It is unclear how intratumor heterogeneity (ITH) contributes to metastasis and how metastatic cells adapt to distant tissue environments. The study of these adaptations is challenged by the limited access to patient material and a lack of experimental models that appropriately recapitulate ITH. To investigate metastatic cell adaptations and the contribution of ITH to metastasis, we analyzed single-cell transcriptomes of matched primary tumors and metastases from patient-derived xenograft models of breast cancer. We found profound transcriptional differences between the primary tumor and metastatic cells. Primary tumors upregulated several metabolic genes, whereas motility pathway genes were upregulated in micrometastases, and stress response signaling was upregulated during progression. Additionally, we identified primary tumor gene signatures that were associated with increased metastatic potential and correlated with patient outcomes. Immune-regulatory control pathways were enriched in poorly metastatic primary tumors, whereas genes involved in epithelial-mesenchymal transition were upregulated in highly metastatic tumors. We found that ITH was dominated by epithelial-mesenchymal plasticity (EMP), which presented as a dynamic continuum with intermediate EMP cell states characterized by specific genes such as CRYAB and S100A2. Elevated expression of an intermediate EMP signature correlated with worse patient outcomes. Our findings identified inhibition of the intermediate EMP cell state as a potential therapeutic target to block metastasis.",,,,,Open Access +PublicationView,CA210184,PS-ON,"Microenvironment, Metastasis, Metabolism",10.1126/sciadv.add0014,Sci Adv,36542704,https://pubmed.ncbi.nlm.nih.gov/36542704,Dissecting the recruitment and self-organization of αSMA-positive fibroblasts in the foreign body response,2022,,"Maria Parlani, Matthew L Bedell, Antonios G Mikos, Peter Friedl, Eleonora Dondossola","The foreign body response (FBR) is a clinically relevant issue that can cause malfunction of implanted medical devices by fibrotic encapsulation. Whereas inflammatory aspects of the FBR have been established, underlying fibroblast-dependent mechanisms remain unclear. We here combine multiphoton microscopy with ad hoc reporter mice expressing α-smooth muscle actin (αSMA) protein to determine the locoregional fibroblast dynamics, activation, and fibrotic encapsulation of polymeric materials. Fibroblasts invaded as individual cells and established a multicellular network, which transited to a two-compartment fibrotic response displaying an αSMA cold external capsule and a long-lasting, inner αSMA hot environment. The recruitment of fibroblasts and extent of fibrosis were only incompletely inhibited after depletion of macrophages, implicating coexistence of macrophage-dependent and macrophage-independent mediators. Furthermore, neither altering material type or porosity modulated αSMA+ cell recruitment and distribution. This identifies fibroblast activation and network formation toward a two-compartment FBR as a conserved, self-organizing process partially independent of macrophages.",,,,,Open Access +PublicationView,CA209992,CSBC,"Microenvironment, Metastasis",10.1002/mco2.174,MedComm (2020),36186235,https://pubmed.ncbi.nlm.nih.gov/36186235,The value of broad taxonomic comparisons in evolutionary medicine: Disease is not a trait but a state of a trait!,2022,"Pregnancy, Comparative Medicine, Evolutionary Medicine, Variational Traits","Mihaela Pavličev, Günter P Wagner","In this short paper, we argue that there is a fundamental connection between the medical sciences and evolutionary biology as both are sciences of biological variation. Medicine studies pathological variation among humans (and domestic animals in veterinary medicine) and evolutionary biology studies variation within and among species in general. A key principle of evolutionary biology is that genetic differences among species have arisen first from mutations originating within populations. This implies a mechanistic continuity between variation among individuals within a species and variation between species. This fact motivates research that seeks to leverage comparisons among species to unravel the genetic basis of human disease vulnerabilities. This view also implies that genetically caused diseases can be understood as extreme states of an underlying trait, that is, an axis of variation, rather than distinct traits, as often assumed in GWAS studies. We illustrate these points with a number of examples as diverse as anatomical birth defects, cranio-facial variation, preeclampsia and vulnerability to metastatic cancer.",,,,,Open Access +PublicationView,CA251443,TEC,"Microenvironment, Drug Resistance/Sensitivity, Platform Development",10.1038/s42003-022-04320-w,Commun Biol,36658332,https://pubmed.ncbi.nlm.nih.gov/36658332,"Biomechanical, biophysical and biochemical modulators of cytoskeletal remodelling and emergent stem cell lineage commitment",2023,,"Vina D L Putra, Kristopher A Kilian, Melissa L Knothe Tate","Across complex, multi-time and -length scale biological systems, redundancy confers robustness and resilience, enabling adaptation and increasing survival under dynamic environmental conditions; this review addresses ubiquitous effects of cytoskeletal remodelling, triggered by biomechanical, biophysical and biochemical cues, on stem cell mechanoadaptation and emergent lineage commitment. The cytoskeleton provides an adaptive structural scaffold to the cell, regulating the emergence of stem cell structure-function relationships during tissue neogenesis, both in prenatal development as well as postnatal healing. Identification and mapping of the mechanical cues conducive to cytoskeletal remodelling and cell adaptation may help to establish environmental contexts that can be used prospectively as translational design specifications to target tissue neogenesis for regenerative medicine. In this review, we summarize findings on cytoskeletal remodelling in the context of tissue neogenesis during early development and postnatal healing, and its relevance in guiding lineage commitment for targeted tissue regeneration. We highlight how cytoskeleton-targeting chemical agents modulate stem cell differentiation and govern responses to mechanical cues in stem cells' emerging form and function. We further review methods for spatiotemporal visualization and measurement of cytoskeletal remodelling, as well as its effects on the mechanical properties of cells, as a function of adaptation. Research in these areas may facilitate translation of stem cells' own healing potential and improve the design of materials, therapies, and devices for regenerative medicine.",,,,,Open Access +PublicationView,CA214354,PS-ON,"Microenvironment, Tumor-Immune",10.1063/1.5129937,APL Bioeng,32095735,https://pubmed.ncbi.nlm.nih.gov/32095735,From cellular to molecular mechanobiology,2020,,"Cheng Zhu, Cho-Yin Lee, Larry V McIntire","Mechanobiology at the cellular level is concerned with what phenotypes that cells exhibit to maintain homeostasis in their normal physiological mechanical environment, as well as what phenotypical changes that cells have to make when their environment is altered. Mechanobiology at the molecular level aims to understand the molecular underpinning of how cells sense, respond to, and adapt to mechanical cues in their environment. In this Perspective, we use our work inspired by and in collaboration with Professor Shu Chien as an example with which we connect the mechanobiology between the cellular and molecular levels. We discuss how physical forces acting on intracellular proteins may impact protein-protein interaction, change protein conformation, crosstalk with biochemical signaling molecules, induce mechanotransduction, and alter the cell structure and function.",,,,,Open Access +PublicationView,CA224013,PDMC,"Microenvironment, Heterogeneity",10.1016/j.celrep.2019.09.056,Cell Rep,31665640,https://pubmed.ncbi.nlm.nih.gov/31665640,Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism,2019,"Glutamine, Glutamine synthetase, Hexosamine, Nucleotide, Pancreatic cancer, nitrogen metabolism, K-ras, Α-ketoglutarate, Glutamate Ammonia Ligase","Alex J Bott, Jianliang Shen, Claudia Tonelli, Le Zhan, Nithya Sivaram, Ya-Ping Jiang, Xufen Yu, Vrushank Bhatt, Eric Chiles, Hua Zhong, Sara Maimouni, Weiwei Dai, Stephani Velasquez, Ji-An Pan, Nathiya Muthalagu, Jennifer Morton, Tracy G Anthony, Hui Feng, Wouter H Lamers, Daniel J Murphy, Jessie Yanxiang Guo, Jian Jin, Howard C Crawford, Lanjing Zhang, Eileen White, Richard Z Lin, Xiaoyang Su, David A Tuveson, Wei-Xing Zong","Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-ketoglutarate (aKG) to fuel the tricarboxylic acid (TCA) cycle. Supporting this notion, aKG supplementation can restore growth/survival of glutamine-deprived cells. However, pancreatic cancers are often poorly vascularized and limited in glutamine supply, in alignment with recent concerns on the significance of glutaminolysis in pancreatic cancer. Here, we show that aKG-mediated rescue of glutamine-deprived pancreatic ductal carcinoma (PDAC) cells requires glutamate ammonia ligase (GLUL), the enzyme responsible for de novo glutamine synthesis. GLUL-deficient PDAC cells are capable of the TCA cycle but defective in aKG-coupled glutamine biosynthesis and subsequent nitrogen anabolic processes. Importantly, GLUL expression is elevated in pancreatic cancer patient samples and in mouse PDAC models. GLUL ablation suppresses the development of KrasG12D-driven murine PDAC. Therefore, GLUL-mediated glutamine biosynthesis couples the TCA cycle with nitrogen anabolism and plays a critical role in PDAC.",,,,,Open Access +PublicationView,CA202177,PS-ON,"Microenvironment, Metastasis",10.1364/optica.6.000076,Optica,31984218,https://pubmed.ncbi.nlm.nih.gov/31984218,Scanless volumetric imaging by selective access multifocal multiphoton microscopy,2019,,"Yi Xue, Kalen P Berry, Josiah R Boivin, Christopher J Rowlands, Yu Takiguchi, Elly Nedivi, Peter T C So","Simultaneous, high-resolution imaging across a large number of synaptic and dendritic sites is critical for understanding how neurons receive and integrate signals. Yet, functional imaging that targets a large number of submicrometer-sized synaptic and dendritic locations poses significant technical challenges. We demonstrate a new parallelized approach to address such questions, increasing the signal-to-noise ratio by an order of magnitude compared to previous approaches. This selective access multifocal multiphoton microscopy uses a spatial light modulator to generate multifocal excitation in three dimensions (3D) and a Gaussian-Laguerre phase plate to simultaneously detect fluorescence from these spots throughout the volume. We test the performance of this system by simultaneously recording Ca2+ dynamics from cultured neurons at 98-118 locations distributed throughout a 3D volume. This is the first demonstration of 3D imaging in a ""single shot"" and permits synchronized monitoring of signal propagation across multiple different dendrites.",,,,,Open Access +PublicationView,CA217376,CSBC,"Microenvironment, Evolution, Epigenetics, Heterogeneity",10.3390/cancers14205008,Cancers (Basel),36291791,https://pubmed.ncbi.nlm.nih.gov/36291791,Comparative Evaluation of Tumor-Infiltrating Lymphocytes in Companion Animals: Immuno-Oncology as a Relevant Translational Model for Cancer Therapy,2022,"Canine, TILs, Neoplasia, Comparative Oncology","Christopher J Pinard, None None, Andrew Lagree, Fang-I Lu, Jonathan Klein, Michelle L Oblak, Roberto Salgado, Juan Carlos Pinto Cardenas, Barbara Brunetti, Luisa Vera Muscatello, Giuseppe Sarli, Maria Pia Foschini, Alexandros Hardas, Simon P Castillo, Khalid AbdulJabbar, Yinyin Yuan, David A Moore, William T Tran","Despite the important role of preclinical experiments to characterize tumor biology and molecular pathways, there are ongoing challenges to model the tumor microenvironment, specifically the dynamic interactions between tumor cells and immune infiltrates. Comprehensive models of host-tumor immune interactions will enhance the development of emerging treatment strategies, such as immunotherapies. Although in vitro and murine models are important for the early modelling of cancer and treatment-response mechanisms, comparative research studies involving veterinary oncology may bridge the translational pathway to human studies. The natural progression of several malignancies in animals exhibits similar pathogenesis to human cancers, and previous studies have shown a relevant and evaluable immune system. Veterinary oncologists working alongside oncologists and cancer researchers have the potential to advance discovery. Understanding the host-tumor-immune interactions can accelerate drug and biomarker discovery in a clinically relevant setting. This review presents discoveries in comparative immuno-oncology and implications to cancer therapy.",,,,,Open Access +PublicationView,"CA217514, CA214300","TEC, PDMC","Microenvironment, Epigenetics, Metastasis, Tumor-Immune",10.1016/j.gendis.2019.10.012,Genes Dis,33997167,https://pubmed.ncbi.nlm.nih.gov/33997167,Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance,2021,"Drug screening, Personalized Medicine, Chromatin Accessibility, Target Discovery, Patient-derived Organoids","Kuei-Ling Tung, Kai-Yuan Chen, Marcos Negrete, Tianyi Chen, Alexias Safi, Abed Alhalim Aljamal, Lingyun Song, Gregory E Crawford, Shengli Ding, David S Hsu, Xiling Shen","Colorectal cancer is a leading cause of cancer deaths. Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies. Here, we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin changes in response to oxaliplatin treatment. Integrated transcriptomic and chromatin accessibility analyses using ATAC-Seq and RNA-Seq identified a group of genes associated with significantly increased chromatin accessibility and upregulated gene expression. CRISPR/Cas9 silencing of fibroblast growth factor receptor 1 (FGFR1) and oxytocin receptor (OXTR) helped overcome oxaliplatin resistance. Similarly, treatment with oxaliplatin in combination with an FGFR1 inhibitor (PD166866) or an antagonist of OXTR (L-368,899) suppressed chemoresistant organoids. However, oxaliplatin treatment did not activate either FGFR1 or OXTR expression in another resistant organoid, suggesting that chromatin accessibility changes are patient-specific. The use of patient-derived cancer organoids in combination with transcriptomic and chromatin profiling may lead to precision treatments to overcome chemoresistance in colorectal cancer.",,,,,Open Access +PublicationView,CA210152,PS-ON,"Microenvironment, Metastasis",10.1016/j.isci.2023.105973,iScience,36756378,https://pubmed.ncbi.nlm.nih.gov/36756378,Regulation of DNA damage response by trimeric G-proteins,2023,"Molecular biology, Cell biology, Biological sciences","Amer Ali Abd El-Hafeez, Nina Sun, Anirban Chakraborty, Jason Ear, Suchismita Roy, Pranavi Chamarthi, Navin Rajapakse, Soumita Das, Kathryn E Luker, Tapas K Hazra, Gary D Luker, Pradipta Ghosh","Upon sensing DNA double-strand breaks (DSBs), eukaryotic cells either die or repair DSBs via one of the two competing pathways, i.e., non-homologous end-joining (NHEJ) or homologous recombination (HR). We show that cell fate after DSBs hinges on GIV/Girdin, a guanine nucleotide-exchange modulator of heterotrimeric Giα•βγ protein. GIV suppresses HR by binding and sequestering BRCA1, a key coordinator of multiple steps within the HR pathway, away from DSBs; it does so using a C-terminal motif that binds BRCA1's BRCT-modules via both phospho-dependent and -independent mechanisms. Using another non-overlapping C-terminal motif GIV binds and activates Gi and enhances the ""free"" Gβγ→PI-3-kinase→Akt pathway, which promotes survival and is known to suppress HR, favor NHEJ. Absence of GIV, or loss of either of its C-terminal motifs enhanced cell death upon genotoxic stress. Because GIV selectively binds other BRCT-containing proteins suggests that G-proteins may fine-tune sensing, repair, and survival after diverse types of DNA damage.",,,,,Open Access +PublicationView,CA214297,PS-ON,"Microenvironment, Metastasis",10.1038/s41698-019-0090-5,NPJ Precis Oncol,31341951,https://pubmed.ncbi.nlm.nih.gov/31341951,Blood-based monitoring identifies acquired and targetable driver HER2 mutations in endocrine-resistant metastatic breast cancer,2019,"Breast cancer, Cancer Genomics","Arielle J Medford, Taronish D Dubash, Dejan Juric, Laura Spring, Andrzej Niemierko, Neelima Vidula, Jeffrey Peppercorn, Steven Isakoff, Brittany A Reeves, Joseph A LiCausi, Benjamin Wesley, Giuliana Malvarosa, Megan Yuen, Ben S Wittner, Michael S Lawrence, A John Iafrate, Leif Ellisen, Beverly Moy, Mehmet Toner, Shyamala Maheswaran, Daniel A Haber, Aditya Bardia","Plasma genotyping identifies potentially actionable mutations at variable mutant allele frequencies, often admixed with multiple subclonal variants, highlighting the need for their clinical and functional validation. We prospectively monitored plasma genotypes in 143 women with endocrine-resistant metastatic breast cancer (MBC), identifying multiple novel mutations including HER2 mutations (8.4%), albeit at different frequencies highlighting clinical heterogeneity. To evaluate functional significance, we established ex vivo culture from circulating tumor cells (CTCs) from a patient with HER2-mutant MBC, which revealed resistance to multiple targeted therapies including endocrine and CDK 4/6 inhibitors, but high sensitivity to neratinib (IC50: 0.018 μM). Immunoblotting analysis of the HER2-mutant CTC culture line revealed high levels of HER2 expression at baseline were suppressed by neratinib, which also abrogated downstream signaling, highlighting oncogenic dependency with HER2 mutation. Furthermore, treatment of an index patient with HER2-mutant MBC with the irreversible HER2 inhibitor neratinib resulted in significant clinical response, with complete molecular resolution of two distinct clonal HER2 mutations, with persistence of other passenger subclones, confirming HER2 alteration as a driver mutation. Thus, driver HER2 mutant alleles that emerge during blood-based monitoring of endocrine-resistant MBC confer novel therapeutic vulnerability, and ex vivo expansion of viable CTCs from the blood circulation may broadly complement plasma-based mutational analysis in MBC.",,,,,Open Access +PublicationView,CA209988,CSBC,"Microenvironment, Heterogeneity, Drug Resistance/Sensitivity",10.1016/j.xcrm.2021.100267,Cell Rep Med,34095877,https://pubmed.ncbi.nlm.nih.gov/34095877,Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma,2021,"MEK, Kidney cancer, VEGFR, Dasatinib, Src, Combination Therapies, Cabozantinib, High Throughput Screen, Non-clear Cell Renal Cell Carcinoma, Cobimetinib","Hui-Wen Lue, Daniel S Derrick, Soumya Rao, Ahna Van Gaest, Larry Cheng, Jennifer Podolak, Samantha Lawson, Changhui Xue, Devin Garg, Ralph White, Christopher W Ryan, Justin M Drake, Anna Ritz, Laura M Heiser, George V Thomas","The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression in vivo. Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.",,,,"GSE171358, SRX10502049, SRX10502048, SRX10502045, SRX10502042, SRX10502046, SRX10502050, SRX10502051, SRX10502052, SRX10502053, SRX10502044, SRP313156, SRX10502047, SRX10502043",Open Access +PublicationView,CA202123,PS-ON,"Metastasis, Heterogeneity",10.1016/j.isci.2021.103252,iScience,34755092,https://pubmed.ncbi.nlm.nih.gov/34755092,A novel jamming phase diagram links tumor invasion to non-equilibrium phase separation,2021,"Cancer, Biophysics, Mechanobiology","Wenying Kang, Jacopo Ferruzzi, Catalina-Paula Spatarelu, Yu Long Han, Yasha Sharma, Stephan A Koehler, Jennifer A Mitchel, Adil Khan, James P Butler, Darren Roblyer, Muhammad H Zaman, Jin-Ah Park, Ming Guo, Zi Chen, Adrian F Pegoraro, Jeffrey J Fredberg","It is well established that the early malignant tumor invades surrounding extracellular matrix (ECM) in a manner that depends upon material properties of constituent cells, surrounding ECM, and their interactions. Recent studies have established the capacity of the invading tumor spheroids to evolve into coexistent solid-like, fluid-like, and gas-like phases. Using breast cancer cell lines invading into engineered ECM, here we show that the spheroid interior develops spatial and temporal heterogeneities in material phase which, depending upon cell type and matrix density, ultimately result in a variety of phase separation patterns at the invasive front. Using a computational approach, we further show that these patterns are captured by a novel jamming phase diagram. We suggest that non-equilibrium phase separation based upon jamming and unjamming transitions may provide a unifying physical picture to describe cellular migratory dynamics within, and invasion from, a tumor.",,,,,Open Access +PublicationView,CA274502,CSBC,"Heterogeneity, Computational Resource",10.3389/fonc.2023.1192208,Front Oncol,37384294,https://pubmed.ncbi.nlm.nih.gov/37384294,Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes,2023,"Drug resistance, Breast cancer, Drug Repurposing, Drug Repositioning, Primary Drug Resistance","Katharine Yu, Amrita Basu, Christina Yau, Denise M Wolf, Hani Goodarzi, Sourav Bandyopadhyay, James E Korkola, Gillian L Hirst, Smita Asare, Angela DeMichele, Nola Hylton, Douglas Yee, Laura Esserman, Laura van 't Veer, Marina Sirota","Introduction: Drug resistance is a major obstacle in cancer treatment and can involve a variety of different factors. Identifying effective therapies for drug resistant tumors is integral for improving patient outcomes. Methods: In this study, we applied a computational drug repositioning approach to identify potential agents to sensitize primary drug resistant breast cancers. We extracted drug resistance profiles from the I-SPY 2 TRIAL, a neoadjuvant trial for early stage breast cancer, by comparing gene expression profiles of responder and non-responder patients stratified into treatments within HR/HER2 receptor subtypes, yielding 17 treatment-subtype pairs. We then used a rank-based pattern-matching strategy to identify compounds in the Connectivity Map, a database of cell line derived drug perturbation profiles, that can reverse these signatures in a breast cancer cell line. We hypothesize that reversing these drug resistance signatures will sensitize tumors to treatment and prolong survival. Results: We found that few individual genes are shared among the drug resistance profiles of different agents. At the pathway level, however, we found enrichment of immune pathways in the responders in 8 treatments within the HR+HER2+, HR+HER2-, and HR-HER2- receptor subtypes. We also found enrichment of estrogen response pathways in the non-responders in 10 treatments primarily within the hormone receptor positive subtypes. Although most of our drug predictions are unique to treatment arms and receptor subtypes, our drug repositioning pipeline identified the estrogen receptor antagonist fulvestrant as a compound that can potentially reverse resistance across 13/17 of the treatments and receptor subtypes including HR+ and triple negative. While fulvestrant showed limited efficacy when tested in a panel of 5 paclitaxel resistant breast cancer cell lines, it did increase drug response in combination with paclitaxel in HCC-1937, a triple negative breast cancer cell line. Conclusion: We applied a computational drug repurposing approach to identify potential agents to sensitize drug resistant breast cancers in the I-SPY 2 TRIAL. We identified fulvestrant as a potential drug hit and showed that it increased response in a paclitaxel-resistant triple negative breast cancer cell line, HCC-1937, when treated in combination with paclitaxel.",,,,,Open Access +PublicationView,CA243075,CSBC,Drug Resistance/Sensitivity,10.1038/s41523-023-00530-5,NPJ Breast Cancer,37059742,https://pubmed.ncbi.nlm.nih.gov/37059742,Integration of clinical features and deep learning on pathology for the prediction of breast cancer recurrence assays and risk of recurrence,2023,,"Frederick M Howard, James Dolezal, Sara Kochanny, Galina Khramtsova, Jasmine Vickery, Andrew Srisuwananukorn, Anna Woodard, Nan Chen, Rita Nanda, Charles M Perou, Olufunmilayo I Olopade, Dezheng Huo, Alexander T Pearson","Gene expression-based recurrence assays are strongly recommended to guide the use of chemotherapy in hormone receptor-positive, HER2-negative breast cancer, but such testing is expensive, can contribute to delays in care, and may not be available in low-resource settings. Here, we describe the training and independent validation of a deep learning model that predicts recurrence assay result and risk of recurrence using both digital histology and clinical risk factors. We demonstrate that this approach outperforms an established clinical nomogram (area under the receiver operating characteristic curve of 0.83 versus 0.76 in an external validation cohort, p = 0.0005) and can identify a subset of patients with excellent prognoses who may not need further genomic testing.",,,,,Open Access +PublicationView,CA250040,PS-ON,Tumor-Immune,10.3389/fimmu.2024.1412513,Front Immunol,39253084,https://pubmed.ncbi.nlm.nih.gov/39253084,"Structure, function, and immunomodulation of the CD8 co-receptor",2024,"Monoclonal antibodies, T cell receptor, Immunomodulation, Major histocompatibility complex, T Cell Signaling, Chimeric Antigen Receptor, Cd8 Co-receptor","Shreyaa Srinivasan, Cheng Zhu, Andrew C McShan","Expressed on the surface of CD8+ T cells, the CD8 co-receptor is a key component of the T cells that contributes to antigen recognition, immune cell maturation, and immune cell signaling. While CD8 is widely recognized as a co-stimulatory molecule for conventional CD8+ αβ T cells, recent reports highlight its multifaceted role in both adaptive and innate immune responses. In this review, we discuss the utility of CD8 in relation to its immunomodulatory properties. We outline the unique structure and function of different CD8 domains (ectodomain, hinge, transmembrane, cytoplasmic tail) in the context of the distinct properties of CD8αα homodimers and CD8αβ heterodimers. We discuss CD8 features commonly used to construct chimeric antigen receptors for immunotherapy. We describe the molecular interactions of CD8 with classical MHC-I, non-classical MHCs, and Lck partners involved in T cell signaling. Engineered and naturally occurring CD8 mutations that alter immune responses are discussed. The applications of anti-CD8 monoclonal antibodies (mABs) that target CD8 are summarized. Finally, we examine the unique structure and function of several CD8/mAB complexes. Collectively, these findings reveal the promising immunomodulatory properties of CD8 and CD8 binding partners, not only to uncover basic immune system function, but to advance efforts towards translational research for targeted immunotherapy.",,,,,Open Access +PublicationView,CA232137,CSBC,"Microenvironment, Heterogeneity, Metabolism",10.46471/gigabyte.77,GigaByte,36949818,https://pubmed.ncbi.nlm.nih.gov/36949818,PhysiCOOL: A generalized framework for model Calibration and Optimization Of modeLing projects,2023,,"Inês G Gonçalves, David A Hormuth, Sandhya Prabhakaran, Caleb M Phillips, José Manuel García-Aznar","In silico models of biological systems are usually very complex and rely on a large number of parameters describing physical and biological properties that require validation. As such, parameter space exploration is an essential component of computational model development to fully characterize and validate simulation results. Experimental data may also be used to constrain parameter space (or enable model calibration) to enhance the biological relevance of model parameters. One widely used computational platform in the mathematical biology community is PhysiCell, which provides a standardized approach to agent-based models of biological phenomena at different time and spatial scales. Nonetheless, one limitation of PhysiCell is the lack of a generalized approach for parameter space exploration and calibration that can be run without high-performance computing access. Here, we present PhysiCOOL, an open-source Python library tailored to create standardized calibration and optimization routines for PhysiCell models.",,,,,Open Access +PublicationView,CA210173,PS-ON,"Microenvironment, Metastasis, Metabolism",10.1002/btm2.10403,Bioeng Transl Med,36925716,https://pubmed.ncbi.nlm.nih.gov/36925716,Vascular stiffening in aging females with a hypertension-induced HIF2A gain-of-function mutation,2023,"Hypertension, Hypoxia, Extracellular matrix, Pulmonary Arterial Hypertension, Hif, Arterial Stiffening, Hif2a, Systemic Arterial Stiffening","Eugenia Volkova, Linda Procell, Lingyang Kong, Lakshmi Santhanam, Sharon Gerecht","Pulmonary arterial hypertension (PAH) is more prevalent in females than males; the causes of this sex difference have not been adequately explored. Gain-of-function (GOF) mutations in hypoxia-inducible factor 2α (HIF2A) lead to PAH and thrombotic consequences in patients and mice. Additionally, multiple emerging studies suggest that elevated systemic arterial stiffening (SAS) occurs in PAH; this could have critical prognostic value. Here, we utilized a HIF2A GOF mouse model to determine how SAS can be used as a prognosticator in sex-divergent PAH. We analyzed survival, vascular mechanics, and vascular phenotypes in young adult (8-16 weeks) and middle age (9-12 months) Hif2a GOF mice. We find that Hif2a heterozygous (HT) female mice, but not Hif2a HT male mice, exhibit poor survival, SAS upon aging, and decreased ability to withstand repeated physiological strain. Hif2a HT female mice also display thickening of the adventitial intima and increased collagen I and collagen III in all layers of the thoracic aorta. Our findings demonstrate differing PAH progression in female and male Hif2a GOF mice. Specifically, alterations in extracellular matrix (ECM) content led to vascular stiffening in aged females, resulting in poor survival. Moreover, we show that SAS emerges early in mice with PAH by coupling studies of vascular mechanics and analyzing vascular structure and composition. Importantly, we present a model for assessing sex differences in hereditary PAH progression and sex-specific prognosis, proposing that aortic stiffening can be used to prognosticate future poor outcomes in PAH.",,,,,Open Access +PublicationView,CA217450,CSBC,"Microenvironment, Heterogeneity, Drug Resistance/Sensitivity",10.21037/tlcr-22-708,Transl Lung Cancer Res,37057106,https://pubmed.ncbi.nlm.nih.gov/37057106,Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review,2023,"Lung cancer, Clinical Trial, acquired resistance, Anaplastic Lymphoma Kinase (Alk)","Aakash Desai, Christine M Lovly","Background and objective: Anaplastic lymphoma kinase (ALK) rearrangements are detected in 3-7% of advanced non-small cell lung cancer (NSCLC). There are currently 5 U.S Food and Drug Administration (FDA)-approved ALK tyrosine kinase inhibitors (TKIs) for the treatment of patients with ALK-positive lung cancer in the advanced/metastatic disease setting. Despite these advances, most patients with ALK-positive lung cancer who are treated with ALK TKI therapy ultimately experience disease progression due to various mechanisms of drug resistance. In this review, we discuss strategies to address acquired therapeutic resistance to ALK inhibition, novel agents and combinatorial strategies in development for both on and off-target resistance, and some emerging approaches to prolong response to ALK inhibitors. Methods: We performed a search of peer-reviewed literature in the English language, conference abstracts, and trial registrations from the MEDLINE (Ovid), Embase (Elsevier), and CENTRAL (Cochrane Library) databases and major international oncology meetings up to August 2022. We then screened for studies describing interventions to overcome ALK resistance based on review of each title and abstract. Key content and findings: For patients with oligo-progression, treatment may include maintaining the same systemic treatment beyond progression while adding local therapies to progressing lesions. Strategies to combat ALK TKI resistance mediated by on-target resistance mechanisms include 4th generation TKIs (TPX-0131, NVL-655) and proteolysis-targeting chimeras (PROTACs) currently in development. While for those patients who develop tumor progression due to off-target (ALK independent) resistance, options may include combination therapies targeting ALK and other downstream or parallel pathways, novel antibody drug conjugates, or combinations of ALK inhibitors with chemotherapy and immunotherapy. Lastly, other potential strategies being explored in the clinic include circulating tumor DNA (ctDNA) surveillance to monitor for molecular mediators of drug resistance prior to frank progression on imaging studies and utilization of ALK TKIs in the adjuvant and neoadjuvant settings. Conclusions: Strategies to overcome resistance to currently available ALK inhibitors are urgently needed. Given the variety of resistance mechanisms, tailormade approaches are required for disease control.",,,,,Open Access +PublicationView,CA217376,CSBC,"Microenvironment, Evolution, Epigenetics, Heterogeneity",10.1038/s41586-024-07747-9,Nature,39112709,https://pubmed.ncbi.nlm.nih.gov/39112709,"The genomic landscape of 2,023 colorectal cancers",2024,,"Alex J Cornish, Andreas J Gruber, Ben Kinnersley, Daniel Chubb, Anna Frangou, Giulio Caravagna, Boris Noyvert, Eszter Lakatos, Henry M Wood, Steve Thorn, Richard Culliford, Claudia Arnedo-Pac, Jacob Househam, William Cross, Amit Sud, Philip Law, Maire Ni Leathlobhair, Aliah Hawari, Connor Woolley, Kitty Sherwood, Nathalie Feeley, Güler Gül, Juan Fernandez-Tajes, Luis Zapata, Ludmil B Alexandrov, Nirupa Murugaesu, Alona Sosinsky, Jonathan Mitchell, Nuria Lopez-Bigas, Philip Quirke, David N Church, Ian P M Tomlinson, Andrea Sottoriva, Trevor A Graham, David C Wedge, Richard S Houlston","Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.",,,,,Open Access +PublicationView,CA217378,CSBC,"Evolution, Heterogeneity, Drug Resistance/Sensitivity",10.1016/j.xpro.2021.100724,STAR Protoc,34401789,https://pubmed.ncbi.nlm.nih.gov/34401789,Quantitative analysis of m6A RNA modification by LC-MS,2021,"Molecular biology, Metabolism, Cell biology, Cell culture, Mass spectrometry, Chemistry","Lavina Mathur, Sunhee Jung, Cholsoon Jang, Gina Lee","N6-adenosine methylation (m6A) of messenger RNA (mRNA) plays key regulatory roles in gene expression. Accurate measurement of m6A levels is thus critical to understand its dynamic changes in various biological settings. Here, we provide a protocol to quantitate the levels of adenosine and m6A in cellular mRNAs. Using nuclease and phosphatase, we digest mRNA into nucleosides, which are subsequently quantified using liquid chromatography mass spectrometry. For complete details on the use and execution of this protocol, please refer to Cho et al. (2021).",,,,,Open Access +PublicationView,CA210173,PS-ON,"Microenvironment, Metastasis, Metabolism",10.1038/s41467-019-12412-1,Nat Commun,31649238,https://pubmed.ncbi.nlm.nih.gov/31649238,Fate-mapping post-hypoxic tumor cells reveals a ROS-resistant phenotype that promotes metastasis,2019,,"Inês Godet, Yu Jung Shin, Julia A Ju, I Chae Ye, Guannan Wang, Daniele M Gilkes","Hypoxia is known to be detrimental in cancer and contributes to its development. In this work, we present an approach to fate-map hypoxic cells in vivo in order to determine their cellular response to physiological O2 gradients as well as to quantify their contribution to metastatic spread. We demonstrate the ability of the system to fate-map hypoxic cells in 2D, and in 3D spheroids and organoids. We identify distinct gene expression patterns in cells that experienced intratumoral hypoxia in vivo compared to cells exposed to hypoxia in vitro. The intratumoral hypoxia gene-signature is a better prognostic indicator for distant metastasis-free survival. Post-hypoxic tumor cells have an ROS-resistant phenotype that provides a survival advantage in the bloodstream and promotes their ability to establish overt metastasis. Post-hypoxic cells retain an increase in the expression of a subset of hypoxia-inducible genes at the metastatic site, suggesting the possibility of a 'hypoxic memory.'",,,,"SRX3779354, SRX3779371, SRX5382138, SRX3779394, SRX3779388, SRX6779672, SRX3779355, SRX3779393, SRX3779396, SRX3779370, GSE111653, SRX3779338, SRX3779372, SRX6779675, SRX3779353, SRX3779345, SRX3779341, SRX3779376, SRX3779343, SRP219888, SRX3779336, SRP185979, SRX3779368, SRX6779674, SRX3779369, SRX3779344, SRX3779398, SRX3779386, SRX3779365, SRX3779382, SRX5382137, SRX3779347, SRX3779385, SRX3779383, SRX3779384, SRP134389, GSE136372, SRX3779337, SRX3779346, SRX3779361, SRX3779362, SRX3779350, SRX3779390, SRX3779373, SRX3779360, SRX3779358, SRX3779367, SRX3779381, SRX3779392, SRX3779375, SRX3779374, SRX3779380, SRX3779348, SRX3779391, GSE126609, SRX3779359, SRX3779387, SRX3779377, SRX3779357, SRX3779366, SRX6779673, SRX3779378, SRX3779339, SRX3779363, SRX3779349, SRX3779340, SRX3779395, SRX3779356, SRX3779351, SRX5382136, SRX3779342, SRX3779399, SRX3779352, SRX3779379, SRX3779364, SRX3779389, SRX3779397, SRX5382135",Open Access +PublicationView,CA274511,CSBC,Metastasis,10.1158/0008-5472.can-23-0046,Cancer Res,37409887,https://pubmed.ncbi.nlm.nih.gov/37409887,Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment,2023,,"Dhanya K Nambiar, Vignesh Viswanathan, Hongbin Cao, Weiruo Zhang, Li Guan, Manish Chamoli, Brittany Holmes, Christina Kong, Rachel Hildebrand, Amanda Jeanette Koong, Rie von Eyben, Sylvia Plevritis, Lingyin Li, Amato Giaccia, Edgar Engleman, Quynh Thu Le","The immune system plays a crucial role in the regulation of metastasis. Tumor cells systemically change immune functions to facilitate metastatic progression. Through this study, we deciphered how tumoral galectin-1 (Gal1) expression shapes the systemic immune environment to promote metastasis in head and neck cancer (HNC). In multiple preclinical models of HNC and lung cancer in immunogenic mice, Gal1 fostered the establishment of a premetastatic niche through polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), which altered the local microenvironment to support metastatic spread. RNA sequencing of MDSCs from premetastatic lungs in these models demonstrated the role of PMN-MDSCs in collagen and extracellular matrix remodeling in the premetastatic compartment. Gal1 promoted MDSC accumulation in the premetastatic niche through the NF-κB signaling axis, triggering enhanced CXCL2-mediated MDSC migration. Mechanistically, Gal1 sustained NF-κB activation in tumor cells by enhancing stimulator of interferon gene (STING) protein stability, leading to prolonged inflammation-driven MDSC expansion. These findings suggest an unexpected protumoral role of STING activation in metastatic progression and establish Gal1 as an endogenous-positive regulator of STING in advanced-stage cancers. Significance: Galectin-1 increases STING stability in cancer cells that activates NF-κB signaling and CXCL2 expression to promote MDSC trafficking, which stimulates the generation of a premetastatic niche and facilitates metastatic progression.",,,,,Open Access +PublicationView,CA209891,CSBC,"Evolution, Heterogeneity, Drug Resistance/Sensitivity",10.1038/s41467-024-52284-8,Nat Commun,39251601,https://pubmed.ncbi.nlm.nih.gov/39251601,MerlinS13 phosphorylation regulates meningioma Wnt signaling and magnetic resonance imaging features,2024,,"Charlotte D Eaton, Lauro Avalos, S John Liu, Zhenhong Chen, Naomi Zakimi, Tim Casey-Clyde, Paola Bisignano, Calixto-Hope G Lucas, Erica Stevenson, Abrar Choudhury, Harish N Vasudevan, Stephen T Magill, Jacob S Young, Nevan J Krogan, Javier E Villanueva-Meyer, Danielle L Swaney, David R Raleigh","Meningiomas are associated with inactivation of NF2/Merlin, but approximately one-third of meningiomas with favorable clinical outcomes retain Merlin expression. Biochemical mechanisms underlying Merlin-intact meningioma growth are incompletely understood, and non-invasive biomarkers that may be used to guide treatment de-escalation or imaging surveillance are lacking. Here, we use single-cell RNA sequencing, proximity-labeling proteomic mass spectrometry, mechanistic and functional approaches, and magnetic resonance imaging (MRI) across meningioma xenografts and patients to define biochemical mechanisms and an imaging biomarker that underlie Merlin-intact meningiomas. We find Merlin serine 13 (S13) dephosphorylation drives meningioma Wnt signaling and tumor growth by attenuating inhibitory interactions with β-catenin and activating the Wnt pathway. MRI analyses show Merlin-intact meningiomas with S13 phosphorylation and favorable clinical outcomes are associated with high apparent diffusion coefficient (ADC). These results define mechanisms underlying a potential imaging biomarker that could be used to guide treatment de-escalation or imaging surveillance for patients with Merlin-intact meningiomas.",,,,,Open Access +PublicationView,CA217376,CSBC,"Microenvironment, Evolution, Epigenetics, Heterogeneity",10.1038/s43018-024-00787-0,Nat Cancer,38997466,https://pubmed.ncbi.nlm.nih.gov/38997466,Tumor evolution metrics predict recurrence beyond 10 years in locally advanced prostate cancer,2024,,"Javier Fernandez-Mateos, George D Cresswell, Nicholas Trahearn, Katharine Webb, Chirine Sakr, Andrea Lampis, Christine Stuttle, Catherine M Corbishley, Vasilis Stavrinides, Luis Zapata, Inmaculada Spiteri, Timon Heide, Lewis Gallagher, Chela James, Daniele Ramazzotti, Annie Gao, Zsofia Kote-Jarai, Ahmet Acar, Lesley Truelove, Paula Proszek, Julia Murray, Alison Reid, Anna Wilkins, Michael Hubank, Ros Eeles, David Dearnaley, Andrea Sottoriva","Cancer evolution lays the groundwork for predictive oncology. Testing evolutionary metrics requires quantitative measurements in controlled clinical trials. We mapped genomic intratumor heterogeneity in locally advanced prostate cancer using 642 samples from 114 individuals enrolled in clinical trials with a 12-year median follow-up. We concomitantly assessed morphological heterogeneity using deep learning in 1,923 histological sections from 250 individuals. Genetic and morphological (Gleason) diversity were independent predictors of recurrence (hazard ratio (HR) = 3.12 and 95% confidence interval (95% CI) = 1.34-7.3; HR = 2.24 and 95% CI = 1.28-3.92). Combined, they identified a group with half the median time to recurrence. Spatial segregation of clones was also an independent marker of recurrence (HR = 2.3 and 95% CI = 1.11-4.8). We identified copy number changes associated with Gleason grade and found that chromosome 6p loss correlated with reduced immune infiltration. Matched profiling of relapse, decades after diagnosis, confirmed that genomic instability is a driving force in prostate cancer progression. This study shows that combining genomics with artificial intelligence-aided histopathology leads to the identification of clinical biomarkers of evolution.",,,,,Open Access +PublicationView,CA251443,TEC,"Microenvironment, Drug Resistance/Sensitivity, Platform Development",10.1016/j.mbplus.2024.100160,Matrix Biol Plus,39291079,https://pubmed.ncbi.nlm.nih.gov/39291079,The importance of matrix in cardiomyogenesis: Defined substrates for maturation and chamber specificity,2024,"Extracellular matrix proteins, Cardiomyocyte differentiation, Cardiomyocyte Maturation, Action Potential Morphology, Array Platform, Chamber Specification","Jake Ireland, Kristopher A Kilian","Human embryonic stem cell-derived cardiomyocytes (hESC-CM) are a promising source of cardiac cells for disease modelling and regenerative medicine. However, current protocols invariably lead to mixed population of cardiac cell types and often generate cells that resemble embryonic phenotypes. Here we developed a combinatorial approach to assess the importance of extracellular matrix proteins (ECMP) in directing the differentiation of cardiomyocytes from human embryonic stem cells (hESC). We did this by focusing on combinations of ECMP commonly found in the developing heart with a broad goal of identifying combinations that promote maturation and influence chamber specific differentiation. We formulated 63 unique ECMP combinations fabricated from collagen 1, collagen 3, collagen 4, fibronectin, laminin, and vitronectin, presented alone and in combinations, leading to the identification of specific ECMP combinations that promote hESC proliferation, pluripotency, and germ layer specification. When hESC were subjected to a differentiation protocol on the ECMP combinations, it revealed precise protein combinations that enhance differentiation as determined by the expression of cardiac progenitor markers kinase insert domain receptor (KDR) and mesoderm posterior transcription factor 1 (MESP1). High expression of cardiac troponin (cTnT) and the relative expression of myosin light chain isoforms (MLC2a and MLC2v) led to the identification of three surfaces that promote a mature cardiomyocyte phenotype. Action potential morphology was used to assess chamber specificity, which led to the identification of matrices that promote chamber-specific cardiomyocytes. This study provides a matrix-based approach to improve control over cardiomyocyte phenotypes during differentiation, with the scope for translation to cardiac laboratory models and for the generation of functional chamber specific cardiomyocytes for regenerative therapies.",,,,,Open Access +PublicationView,CA243075,CSBC,Drug Resistance/Sensitivity,10.3390/cancers16172942,Cancers (Basel),39272799,https://pubmed.ncbi.nlm.nih.gov/39272799,Agent-Based Modeling of Virtual Tumors Reveals the Critical Influence of Microenvironmental Complexity on Immunotherapy Efficacy,2024,"Bladder cancer, Cytotoxic T lymphocyte, Ordinary differential equation, Agent-based Model, Immune Checkpoint Inhibition, Fas/fas Ligand, Tumor Antigenicity, Perforin/granzyme","Yixuan Wang, Daniel R Bergman, Erica Trujillo, Anthony A Fernald, Lie Li, Alexander T Pearson, Randy F Sweis, Trachette L Jackson","Since the introduction of the first immune checkpoint inhibitor (ICI), immunotherapy has changed the landscape of molecular therapeutics for cancers. However, ICIs do not work equally well on all cancers and for all patients. There has been a growing interest in using mathematical and computational models to optimize clinical responses. Ordinary differential equations (ODEs) have been widely used for mechanistic modeling in immuno-oncology and immunotherapy. They allow rapid simulations of temporal changes in the cellular and molecular populations involved. Nonetheless, ODEs cannot describe the spatial structure in the tumor microenvironment or quantify the influence of spatially-dependent characteristics of tumor-immune dynamics. For these reasons, agent-based models (ABMs) have gained popularity because they can model more detailed phenotypic and spatial heterogeneity that better reflect the complexity seen in vivo. In the context of anti-PD-1 ICIs, we compare treatment outcomes simulated from an ODE model and an ABM to show the importance of including spatial components in computational models of cancer immunotherapy. We consider tumor cells of high and low antigenicity and two distinct cytotoxic T lymphocyte (CTL) killing mechanisms. The preferred mechanism differs based on the antigenicity of tumor cells. Our ABM reveals varied phenotypic shifts within the tumor and spatial organization of tumor and CTLs despite similarities in key immune parameters, initial simulation conditions, and early temporal trajectories of the cell populations.",,,,,Open Access +PublicationView,CA217378,CSBC,"Evolution, Heterogeneity, Drug Resistance/Sensitivity",10.1186/s12859-024-05926-z,BMC Bioinformatics,39294560,https://pubmed.ncbi.nlm.nih.gov/39294560,Leveraging gene correlations in single cell transcriptomic data,2024,"Melanoma, Gene Regulatory Network, Gene Co-expression Network, Single Cell Rna Sequencing, Gene–gene Correlation","Kai Silkwood, Emmanuel Dollinger, Joshua Gervin, Scott Atwood, Qing Nie, Arthur D Lander","Background: Many approaches have been developed to overcome technical noise in single cell RNA-sequencing (scRNAseq). As researchers dig deeper into data-looking for rare cell types, subtleties of cell states, and details of gene regulatory networks-there is a growing need for algorithms with controllable accuracy and fewer ad hoc parameters and thresholds. Impeding this goal is the fact that an appropriate null distribution for scRNAseq cannot simply be extracted from data in which ground truth about biological variation is unknown (i.e., usually). Results: We approach this problem analytically, assuming that scRNAseq data reflect only cell heterogeneity (what we seek to characterize), transcriptional noise (temporal fluctuations randomly distributed across cells), and sampling error (i.e., Poisson noise). We analyze scRNAseq data without normalization-a step that skews distributions, particularly for sparse data-and calculate p values associated with key statistics. We develop an improved method for selecting features for cell clustering and identifying gene-gene correlations, both positive and negative. Using simulated data, we show that this method, which we call BigSur (Basic Informatics and Gene Statistics from Unnormalized Reads), captures even weak yet significant correlation structures in scRNAseq data. Applying BigSur to data from a clonal human melanoma cell line, we identify thousands of correlations that, when clustered without supervision into gene communities, align with known cellular components and biological processes, and highlight potentially novel cell biological relationships. Conclusions: New insights into functionally relevant gene regulatory networks can be obtained using a statistically grounded approach to the identification of gene-gene correlations.",,,,,Open Access +PublicationView,"CA261694, CA268084","CCBIR, MetNet","Metastasis, Method/Assay Development, Epigenetics, Computational Model Development, Platform Development",10.7554/elife.97604,Elife,39331520,https://pubmed.ncbi.nlm.nih.gov/39331520,"Local volume concentration, packing domains, and scaling properties of chromatin",2024,"Theory, chromatin, None, Physics Of Living Systems, Sr-ev","Marcelo A Carignano, Martin Kroeger, Luay M Almassalha, Vasundhara Agrawal, Wing Shun Li, Emily M Pujadas-Liwag, Rikkert J Nap, Vadim Backman, Igal Szleifer","We propose the Self Returning Excluded Volume (SR-EV) model for the structure of chromatin based on stochastic rules and physical interactions. The SR-EV rules of return generate conformationally defined domains observed by single-cell imaging techniques. From nucleosome to chromosome scales, the model captures the overall chromatin organization as a corrugated system, with dense and dilute regions alternating in a manner that resembles the mixing of two disordered bi-continuous phases. This particular organizational topology is a consequence of the multiplicity of interactions and processes occurring in the nuclei, and mimicked by the proposed return rules. Single configuration properties and ensemble averages show a robust agreement between theoretical and experimental results including chromatin volume concentration, contact probability, packing domain identification and size characterization, and packing scaling behavior. Model and experimental results suggest that there is an inherent chromatin organization regardless of the cell character and resistant to an external forcing such as RAD21 degradation.",,,,,Open Access +PublicationView,CA244100,PS-ON,"Drug Resistance/Sensitivity, Tumor-Immune",10.1186/s13014-024-02514-6,Radiat Oncol,39272128,https://pubmed.ncbi.nlm.nih.gov/39272128,Spatially fractionated GRID radiation potentiates immune-mediated tumor control,2024,"mathematical model, Personalized Oncology, Spatially Fractionated Radiotherapy, Tumor Immune Interactions","Rebecca A Bekker, Nina Obertopp, Gage Redler, José Penagaricano, Jimmy J Caudell, Kosj Yamoah, Shari Pilon-Thomas, Eduardo G Moros, Heiko Enderling","Background: Tumor-immune interactions shape a developing tumor and its tumor immune microenvironment (TIME) resulting in either well-infiltrated, immunologically inflamed tumor beds, or immune deserts with low levels of infiltration. The pre-treatment immune make-up of the TIME is associated with treatment outcome; immunologically inflamed tumors generally exhibit better responses to radio- and immunotherapy than non-inflamed tumors. However, radiotherapy is known to induce opposing immunological consequences, resulting in both immunostimulatory and inhibitory responses. In fact, it is thought that the radiation-induced tumoricidal immune response is curtailed by subsequent applications of radiation. It is thus conceivable that spatially fractionated radiotherapy (SFRT), administered through GRID blocks (SFRT-GRID) or lattice radiotherapy to create areas of low or high dose exposure, may create protective reservoirs of the tumor immune microenvironment, thereby preserving anti-tumor immune responses that are pivotal for radiation success. Methods: We have developed an agent-based model (ABM) of tumor-immune interactions to investigate the immunological consequences and clinical outcomes after 2Gy×35 whole tumor radiation therapy (WTRT) and SFRT-GRID. The ABM is conceptually calibrated such that untreated tumors escape immune surveillance and grow to clinical detection. Individual ABM simulations are initialized from four distinct multiplex immunohistochemistry (mIHC) slides, and immune related parameter rates are generated using Latin Hypercube Sampling. Results: In silico simulations suggest that radiation-induced cancer cell death alone is insufficient to clear a tumor with WTRT. However, explicit consideration of radiation-induced anti-tumor immunity synergizes with radiation cytotoxicity to eradicate tumors. Similarly, SFRT-GRID is successful with radiation-induced anti-tumor immunity, and, for some pre-treatment TIME compositions and modeling parameters, SFRT-GRID might be superior to WTRT in providing tumor control. Conclusion: This study demonstrates the pivotal role of the radiation-induced anti-tumor immunity. Prolonged fractionated treatment schedules may counteract early immune recruitment, which may be protected by SFRT-facilitated immune reservoirs. Different biological responses and treatment outcomes are observed based on pre-treatment TIME composition and model parameters. A rigorous analysis and model calibration for different tumor types and immune infiltration states is required before any conclusions can be drawn for clinical translation.",,,,,Open Access +PublicationView,CA274499,CSBC,"Oncogenic Stress, Metabolism",10.1038/s44320-024-00064-3,Mol Syst Biol,39333715,https://pubmed.ncbi.nlm.nih.gov/39333715,Proteome-wide copy-number estimation from transcriptomics,2024,"CVB3, Tmt, Ccle, Swath, Pinferna","Andrew J Sweatt, Cameron D Griffiths, Sarah M Groves, B Bishal Paudel, Lixin Wang, David F Kashatus, Kevin A Janes","Protein copy numbers constrain systems-level properties of regulatory networks, but proportional proteomic data remain scarce compared to RNA-seq. We related mRNA to protein statistically using best-available data from quantitative proteomics and transcriptomics for 4366 genes in 369 cell lines. The approach starts with a protein's median copy number and hierarchically appends mRNA-protein and mRNA-mRNA dependencies to define an optimal gene-specific model linking mRNAs to protein. For dozens of cell lines and primary samples, these protein inferences from mRNA outmatch stringent null models, a count-based protein-abundance repository, empirical mRNA-to-protein ratios, and a proteogenomic DREAM challenge winner. The optimal mRNA-to-protein relationships capture biological processes along with hundreds of known protein-protein complexes, suggesting mechanistic relationships. We use the method to identify a viral-receptor abundance threshold for coxsackievirus B3 susceptibility from 1489 systems-biology infection models parameterized by protein inference. When applied to 796 RNA-seq profiles of breast cancer, inferred copy-number estimates collectively re-classify 26-29% of luminal tumors. By adopting a gene-centered perspective of mRNA-protein covariation across different biological contexts, we achieve accuracies comparable to the technical reproducibility of contemporary proteomics.",,,,,Open Access +PublicationView,"CA225566, CA253540","PS-ON, CSBC","Microenvironment, Heterogeneity, Drug Resistance/Sensitivity",10.1073/pnas.2403062121,Proc Natl Acad Sci U S A,39302966,https://pubmed.ncbi.nlm.nih.gov/39302966,Genetic variation drives cancer cell adaptation to ECM stiffness,2024,"Cancer, Mechanobiology, Ecm Stiffness, Mechanoadaptation","Ting-Ching Wang, Suchitaa Sawhney, Daylin Morgan, Richard L Bennett, Richa Rashmi, Marcos R Estecio, Amy Brock, Irtisha Singh, Charles F Baer, Jonathan D Licht, Tanmay P Lele","The progression of many solid tumors is accompanied by temporal and spatial changes in the stiffness of the extracellular matrix (ECM). Cancer cells adapt to soft and stiff ECM through mechanisms that are not fully understood. It is well known that there is significant genetic heterogeneity from cell to cell in tumors, but how ECM stiffness as a parameter might interact with that genetic variation is not known. Here, we employed experimental evolution to study the response of genetically variable and clonal populations of tumor cells to variable ECM stiffness. Proliferation rates of genetically variable populations cultured on soft ECM increased over a period of several weeks, whereas clonal populations did not evolve. Tracking of DNA barcoded cell lineages revealed that soft ECM consistently selected for the same few variants. These data provide evidence that ECM stiffness exerts natural selection on genetically variable tumor populations. Soft-selected cells were highly migratory, with enriched oncogenic signatures and unusual behaviors such as spreading and traction force generation on ECMs with stiffness as low as 1 kPa. Rho-regulated cell spreading was found to be the directly selected trait, with yes-associated protein 1 translocation to the nucleus mediating fitness on soft ECM. Overall, these data show that genetic variation can drive cancer cell adaptation to ECM stiffness.",,,,"SRX23623627, SRP489796, SRX23623621, SRX23623632, SRX23623631, SRX23623625, SRX23623633, SRX23623629, SRX23623626, SRX23623622, SRX23623630, SRX23623635, SRX23623634, GSE255829, SRX23623628, SRX23623624, SRX23623620, SRX23623623",Open Access +PublicationView,CA225088,CSBC,"Microenvironment, Drug Resistance/Sensitivity",10.1016/j.celrep.2024.114552,Cell Rep,39068660,https://pubmed.ncbi.nlm.nih.gov/39068660,ASCT2 is a major contributor to serine uptake in cancer cells,2024,"Diet, Breast cancer, Purine Biosynthesis, Cancer Metabolism, Amino Acid Uptake, Erα, Asct2, Slc1a5, Serine Transporter, Serine Starvation, Cp: Cancer","Kelly O Conger, Christopher Chidley, Mete Emir Ozgurses, Huiping Zhao, Yumi Kim, Svetlana E Semina, Philippa Burns, Vipin Rawat, Lina Lietuvninkas, Ryan Sheldon, Issam Ben-Sahra, Jonna Frasor, Peter K Sorger, Gina M DeNicola, Jonathan L Coloff","The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo, others are auxotrophic and therefore reliant on serine uptake. Importantly, despite several transporters being known to be capable of transporting serine, the transporters that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (SLC1A5) as a major contributor to serine uptake in cancer cells. ASCT2 is well known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that estrogen receptor α (ERα) promotes serine uptake by directly activating SLC1A5 transcription. Collectively, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target.",,,,,Open Access +PublicationView,CA224012,PDMC,"Drug Resistance/Sensitivity, Heterogeneity, Experimental Model Development",10.1158/0008-5472.can-23-1895,Cancer Res,38843355,https://pubmed.ncbi.nlm.nih.gov/38843355,IDH1 Inhibition Potentiates Chemotherapy Efficacy in Pancreatic Cancer,2024,,"Mehrdad Zarei, Omid Hajihassani, Jonathan J Hue, Alexander W Loftus, Hallie J Graor, Faith Nakazzi, Parnian Naji, Christina S Boutros, Vinayak Uppin, Ali Vaziri-Gohar, Akram S Shalaby, John M Asara, Luke D Rothermel, Jonathan R Brody, Jordan M Winter","Pancreatic ductal adenocarcinoma (PDAC) is associated with a 5-year overall survival rate of just 13%, and development of chemotherapy resistance is nearly universal. PDAC cells overexpress wild-type isocitrate dehydrogenase 1 (IDH1) that can enable them to overcome metabolic stress, suggesting it could represent a therapeutic target in PDAC. Here, we found that anti-IDH1 therapy enhanced the efficacy of conventional chemotherapeutics. Chemotherapy treatment induced reactive oxygen species (ROS) and increased tricarboxylic acid cycle activity in PDAC cells, along with the induction of wild-type IDH1 expression as a key resistance factor. IDH1 facilitated PDAC survival following chemotherapy treatment by supporting mitochondrial function and antioxidant defense to neutralize ROS through the generation of α-ketoglutarate and NADPH, respectively. Pharmacologic inhibition of wild-type IDH1 with ivosidenib synergized with conventional chemotherapeutics in vitro and potentiated the efficacy of subtherapeutic doses of these drugs in vivo in murine PDAC models. This promising treatment approach is translatable through available and safe oral inhibitors and provides the basis of an open and accruing clinical trial testing this combination (NCT05209074). Significance: Targeting IDH1 improves sensitivity to chemotherapy by suppressing mitochondrial function and inducing oxidative stress, supporting the potential of the combination as an effective strategy for treating pancreatic cancer.",,,,,Open Access +PublicationView,"CA274511, CA209971",CSBC,"Microenvironment, Metastasis, Tumor-Immune",10.1038/s41467-024-52394-3,Nat Commun,39289380,https://pubmed.ncbi.nlm.nih.gov/39289380,Basal-to-inflammatory transition and tumor resistance via crosstalk with a pro-inflammatory stromal niche,2024,,"Nancy Yanzhe Li, Weiruo Zhang, Daniel Haensel, Anna R Jussila, Cory Pan, Sadhana Gaddam, Sylvia K Plevritis, Anthony E Oro","Cancer-associated inflammation is a double-edged sword possessing both pro- and anti-tumor properties through ill-defined tumor-immune dynamics. While we previously identified a carcinoma tumor-intrinsic resistance pathway, basal-to-squamous cell carcinoma transition, here, employing a multipronged single-cell and spatial-omics approach, we identify an inflammation and therapy-enriched tumor state we term basal-to-inflammatory transition. Basal-to-inflammatory transition signature correlates with poor overall patient survival in many epithelial tumors. Basal-to-squamous cell carcinoma transition and basal-to-inflammatory transition occur in adjacent but distinct regions of a single tumor: basal-to-squamous cell carcinoma transition arises within the core tumor nodule, while basal-to-inflammatory transition emerges from a specialized inflammatory environment defined by a tumor-associated TREM1 myeloid signature. TREM1 myeloid-derived cytokines IL1 and OSM induce basal-to-inflammatory transition in vitro and in vivo through NF-κB, lowering sensitivity of patient basal cell carcinoma explant tumors to Smoothened inhibitor treatment. This work deepens our knowledge of the heterogeneous local tumor microenvironment and nominates basal-to-inflammatory transition as a drug-resistant but targetable tumor state driven by a specialized inflammatory microenvironment.",,,,,Open Access +PublicationView,CA209975,CSBC,"Drug Resistance/Sensitivity, Microenvironment, Metastasis, Tumor-Immune",10.1084/jem.20231193,J Exp Med,39321257,https://pubmed.ncbi.nlm.nih.gov/39321257,Precursor central memory versus effector cell fate and naïve CD4+ T cell heterogeneity,2024,,"Deeksha Deep, Herman Gudjonson, Chrysothemis C Brown, Samuel A Rose, Roshan Sharma, Yoselin A Paucar Iza, Seunghee Hong, Saskia Hemmers, Michail Schizas, Zhong-Min Wang, Yuezhou Chen, Duane R Wesemann, Virginia Pascual, Dana Pe'er, Alexander Y Rudensky","Upon antigenic stimulation, naïve CD4+ T cells can give rise to phenotypically distinct effector T helper cells and long-lived memory T cells. We computationally reconstructed the in vivo trajectory of CD4+ T cell differentiation during a type I inflammatory immune response and identified two distinct differentiation paths for effector and precursor central memory T cells arising directly from naïve CD4+ T cells. Unexpectedly, our studies revealed heterogeneity among naïve CD4+ T cells, which are typically considered homogeneous save for their diverse T cell receptor usage. Specifically, a previously unappreciated population of naïve CD4+ T cells sensing environmental type I IFN exhibited distinct activation thresholds, suggesting that naïve CD4+ T cell differentiation potential may be influenced by environmental cues. This population was expanded in human viral infection and type I IFN response-lined autoimmunity. Understanding the relevance of naïve T cell heterogeneity to beneficial and maladaptive T cell responses may have therapeutic implications for adoptive T cell therapies in cancer immunotherapy and vaccination.",,,,,Open Access +PublicationView,CA227550,CSBC,"Heterogeneity, Drug Resistance/Sensitivity",10.1016/j.celrep.2024.114721,Cell Rep,39255061,https://pubmed.ncbi.nlm.nih.gov/39255061,Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma,2024,"Melanoma, Aging, Angiogenesis, Fibroblasts, Exosomes, Extracellular Vesicles, Cd9, Cp: Cancer, Angioepoetin Ligand 2 (Angptl2)","Laura Hüser, Yash Chhabra, Olesia Gololobova, Vania Wang, Guanshu Liu, Agrani Dixit, Murilo Ramos Rocha, Elizabeth I Harper, Mitchell E Fane, Gloria E Marino-Bravante, Daniel J Zabransky, Kathy Q Cai, Jochen Utikal, Barbara S Slusher, Jeremy Walston, Evan J Lipson, Kenneth W Witwer, Ashani T Weeraratna","Advancing age is a negative prognostic factor for cutaneous melanoma. However, the role of extracellular vesicles (EVs) within the melanoma tumor microenvironment (TME) has remained unexplored in the context of aging. While the size and morphology of the EVs isolated from young vs. aged fibroblasts remained unaltered, the contents of the protein cargo were changed. Aging reduced the expression of the tetraspanin CD9 in both the dermal fibroblasts and released EVs. CD9 is a crucial regulator of EV cargo sorting. Modulating the CD9 expression in fibroblasts was sufficient to alter its levels in EVs. Mass spectrometry analysis of EVs released by CD9 knockdown (KD) vs. control cells revealed a significant increase in angiopoietin-like protein 2 (ANGPTL2), an angiogenesis promoter. Analysis of primary endothelial cells confirmed increased sprouting under CD9 KD conditions. Together, our data indicate that aged EVs play an important role in promoting a tumor-permissive microenvironment.",,,,,Open Access +PublicationView,"CA280849, CA244100",PS-ON,"Drug Resistance/Sensitivity, Microenvironment, Tumor-Immune, Computational Model Development",10.1038/s41416-024-02844-y,Br J Cancer,39261715,https://pubmed.ncbi.nlm.nih.gov/39261715,Fractionated photoimmunotherapy stimulates an anti-tumour immune response: an integrated mathematical and in vitro study,2024,,"Mohammad U Zahid, Matthew Waguespack, Rebecca C Harman, Eric M Kercher, Shubhankar Nath, Tayyaba Hasan, Imran Rizvi, Bryan Q Spring, Heiko Enderling","Background: Advanced epithelial ovarian cancer (EOC) has high recurrence rates due to disseminated initial disease presentation. Cytotoxic phototherapies, such as photodynamic therapy (PDT) and photoimmunotherapy (PIT, cell-targeted PDT), have the potential to treat disseminated malignancies due to safe intraperitoneal delivery. Methods: We use in vitro measurements of EOC tumour cell and T cell responses to chemotherapy, PDT, and epidermal growth factor receptor targeted PIT as inputs to a mathematical model of non-linear tumour and immune effector cell interaction. The model outputs were used to calculate how photoimmunotherapy could be utilised for tumour control. Results: In vitro measurements of PIT dose responses revealed that although low light doses (<10 J/cm2) lead to limited tumour cell killing they also increased proliferation of anti-tumour immune effector cells. Model simulations demonstrated that breaking up a larger light dose into multiple lower dose fractions (vis-à-vis fractionated radiotherapy) could be utilised to effect tumour control via stimulation of an anti-tumour immune response. Conclusions: There is promise for applying fractionated PIT in the setting of EOC. However, recommending specific fractionated PIT dosimetry and timing will require appropriate model calibration on tumour-immune interaction data in human patients and subsequent validation of model predictions in prospective clinical trials.",,,,,Open Access +PublicationView,CA241927,TEC,"Microenvironment, Metastasis",10.1016/j.xpro.2024.103266,STAR Protoc,39146187,https://pubmed.ncbi.nlm.nih.gov/39146187,Protocol for in vitro evaluation of effects of stiffness on patient-derived glioblastoma,2024,"Cancer, Tissue engineering, Material Sciences","Alireza Sohrabi, Stephanie K Seidlits","Glioblastoma (GBM) is the most common and lethal type of primary brain tumor. Physiologically, GBM cells experience a heterogeneous mechanical landscape. Here, we present an in vitro method to study the effects of tissue stiffness on patient-derived GBM that utilizes hyaluronic acid (HA)-based, mechanically tunable scaffolds for three-dimensional (3D) culture of patient-derived GBM spheroids. We describe steps to fabricate and characterize HA-based scaffolds, culture GBM spheroids within 3D hydrogel scaffolds, and prepare cultured cells for a variety of experimental assessments. For complete details on the use and execution of this protocol, please refer to Sohrabi et al.1.",,,,,Open Access +PublicationView,CA238720,CSBC,Drug Resistance/Sensitivity,10.1016/j.crmeth.2023.100483,Cell Rep Methods,37323574,https://pubmed.ncbi.nlm.nih.gov/37323574,Decrypting the potency of anti-cancer therapeutics by using mass spectrometry to quantify post-translational modifications,2023,,"Sophie A Herbst, Forest M White","In a recent issue of Science, Zecha et al.1 present decryptM, an approach aimed at defining the mechanisms of action of anti-cancer therapeutics through systems-level analysis of protein post-translational modifications (PTMs). By using a broad range of concentrations, decryptM generates drug response curves for each detected PTM, enabling identification of drug effects at different therapeutic doses.",,,,,Open Access +PublicationView,CA217377,CSBC,"Microenvironment, Drug Resistance/Sensitivity",10.1038/s41467-018-07478-2,Nat Commun,30487575,https://pubmed.ncbi.nlm.nih.gov/30487575,Selective expansion of myeloid and NK cells in humanized mice yields human-like vaccine responses,2018,,"Florian Douam, Carly G K Ziegler, Gabriela Hrebikova, Bruno Fant, Robert Leach, Lance Parsons, Wei Wang, Jenna M Gaska, Benjamin Y Winer, Brigitte Heller, Alex K Shalek, Alexander Ploss","Mice engrafted with components of a human immune system have become widely-used models for studying aspects of human immunity and disease. However, a defined methodology to objectively measure and compare the quality of the human immune response in different models is lacking. Here, by taking advantage of the highly immunogenic live-attenuated yellow fever virus vaccine YFV-17D, we provide an in-depth comparison of immune responses in human vaccinees, conventional humanized mice, and second generation humanized mice. We demonstrate that selective expansion of human myeloid and natural killer cells promotes transcriptomic responses akin to those of human vaccinees. These enhanced transcriptomic profiles correlate with the development of an antigen-specific cellular and humoral response to YFV-17D. Altogether, our approach provides a robust scoring of the quality of the human immune response in humanized mice and highlights a rational path towards developing better pre-clinical models for studying the human immune response and disease.",,,,"GSE119749, GSE119750, GSE119751",Open Access +PublicationView,CA232517,TEC,"Microenvironment, Metastasis",10.1007/978-1-0716-1956-8_6,Methods Mol Biol,34918289,https://pubmed.ncbi.nlm.nih.gov/34918289,Multispectral Staining and Analysis of Extracellular Matrix,2022,"Ovarian cancer, Stic, Serous Tubal Intra-epithelial Carcinoma","Carine M Renner, Mike R Visetsouk, Pamela K Kreeger, Kristyn S Masters","Multiplexed immunofluorescent (IF) techniques enable the detection of multiple antigens within the same sample and are therefore useful in situations where samples are rare or small in size. Similar to standard IF, multiplexed IF yields information on both the location and relative amount of detected antigens. While this method has been used primarily to detail cell phenotypes, we have recently adapted it to profile the extracellular matrix (ECM), which provides technical challenges due to autofluorescence and spatial overlap. This chapter details the planning, execution, optimization, and troubleshooting to use multiplexed IF to profile the ECM of human fallopian tube tissue.",,,,,Open Access +PublicationView,,,,10.1016/j.actbio.2024.08.026,Acta Biomater,39182805,https://pubmed.ncbi.nlm.nih.gov/39182805,Multiphoton excited polymerized biomimetic models of collagen fiber morphology to study single cell and collective migration dynamics in pancreatic cancer,2024,"Pancreatic cancer, Collective Migration, Single Cell Migration, Multiphoton Excited Fabrication, Collagen Fibers, Collagen Remodeling","Sophie Mancha, Meghan Horan, Ojaswi Pasachhe, Adib Keikhosravi, Kevin W Eliceiri, Kristina A Matkowskyj, Jacob Notbohm, Melissa C Skala, Paul J Campagnola","The respective roles of aligned collagen fiber morphology found in the extracellular matrix (ECM) of pancreatic cancer patients and cellular migration dynamics have been gaining attention because of their connection with increased aggressive phenotypes and poor prognosis. To better understand how collagen fiber morphology influences cell-matrix interactions associated with metastasis, we used Second Harmonic Generation (SHG) images from patient biopsies with Pancreatic ductal adenocarcinoma (PDAC) as models to fabricate collagen scaffolds to investigate processes associated with motility. Using the PDAC BxPC-3 metastatic cell line, we investigated single and collective cell dynamics on scaffolds of varying collagen alignment. Collective or clustered cells grown on the scaffolds with the highest collagen fiber alignment had increased E-cadherin expression and larger focal adhesion sites compared to single cells, consistent with metastatic behavior. Analysis of single cell motility revealed that the dynamics were characterized by random walk on all substrates. However, examining collective motility over different time points showed that the migration was super-diffusive and enhanced on highly aligned fibers, whereas it was hindered and sub-diffusive on un-patterned substrates. This was further supported by the more elongated morphology observed in collectively migrating cells on aligned collagen fibers. Overall, this approach allows the decoupling of single and collective cell behavior as a function of collagen alignment and shows the relative importance of collective cell behavior as well as fiber morphology in PDAC metastasis. We suggest these scaffolds can be used for further investigations of PDAC cell biology. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate, where aligned collagen has been associated with poor prognosis. Biomimetic models representing this architecture are needed to understand complex cellular interactions. The SHG image-based models based on stromal collagen from human biopsies afford the measurements of cell morphology, cadherin and focal adhesion expression as well as detailed motility dynamics. Using a metastatic cell line, we decoupled the roles of single cell and collective cell behavior as well as that arising from aligned collagen. Our data suggests that metastatic characteristics are enhanced by increased collagen alignment and that collective cell behavior is more relevant to metastatic processes. These scaffolds provide new insight in this disease and can be a platform for further experiments such as testing drug efficacy.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA261694,MetNet,"Method/Assay Development, Metastasis",10.1016/j.cell.2024.07.036,Cell,39178829,https://pubmed.ncbi.nlm.nih.gov/39178829,Multiphoton fluorescence microscopy for in vivo imaging,2024,,"Chris Xu, Maiken Nedergaard, Deborah J Fowell, Peter Friedl, Na Ji","Multiphoton fluorescence microscopy (MPFM) has been a game-changer for optical imaging, particularly for studying biological tissues deep within living organisms. MPFM overcomes the strong scattering of light in heterogeneous tissue by utilizing nonlinear excitation that confines fluorescence emission mostly to the microscope focal volume. This enables high-resolution imaging deep within intact tissue and has opened new avenues for structural and functional studies. MPFM has found widespread applications and has led to numerous scientific discoveries and insights into complex biological processes. Today, MPFM is an indispensable tool in many research communities. Its versatility and effectiveness make it a go-to technique for researchers investigating biological phenomena at the cellular and subcellular levels in their native environments. In this Review, the principles, implementations, capabilities, and limitations of MPFM are presented. Three application areas of MPFM, neuroscience, cancer biology, and immunology, are reviewed in detail and serve as examples for applying MPFM to biological research.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA268072,CCBIR,"Metastasis, Platform Development",10.1038/s41592-024-02413-4,Nat Methods,39261640,https://pubmed.ncbi.nlm.nih.gov/39261640,Navigate: an open-source platform for smart light-sheet microscopy,2024,,"Zach Marin, Xiaoding Wang, Dax W Collison, Conor McFadden, Jinlong Lin, Hazel M Borges, Bingying Chen, Dushyant Mehra, Qionghua Shen, Seweryn Gałecki, Stephan Daetwyler, Steven J Sheppard, Phu Thien, Baylee A Porter, Suzanne D Conzen, Douglas P Shepherd, Reto Fiolka, Kevin M Dean",No abstract available.,Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA263001,MetNet,"Metastasis, Microenvironment, Heterogeneity",10.1111/pcmr.13195,Pigment Cell Melanoma Res,39254030,https://pubmed.ncbi.nlm.nih.gov/39254030,MetFinder: A Tool for Automated Quantitation of Metastatic Burden in Histological Sections From Preclinical Models,2024,"Histopathology, Quantification, Preclinical Studies, Whole Slide Images, Murine Models, Deep Learning, Metastatic Burden","Alcida Karz, Nicolas Coudray, Erol Bayraktar, Kristyn Galbraith, George Jour, Arman Alberto Sorin Shadaloey, Nicole Eskow, Andrey Rubanov, Maya Navarro, Rana Moubarak, Gillian Baptiste, Grace Levinson, Valeria Mezzano, Mark Alu, Cynthia Loomis, Daniel Lima, Adam Rubens, Lucia Jilaveanu, Aristotelis Tsirigos, Eva Hernando","As efforts to study the mechanisms of melanoma metastasis and novel therapeutic approaches multiply, researchers need accurate, high-throughput methods to evaluate the effects on tumor burden resulting from specific interventions. We show that automated quantification of tumor content from whole slide images is a compelling solution to assess in vivo experiments. In order to increase the outflow of data collection from preclinical studies, we assembled a large dataset with annotations and trained a deep neural network for the quantitative analysis of melanoma tumor content on histopathological sections of murine models. After assessing its performance in segmenting these images, the tool obtained consistent results with an orthogonal method (bioluminescence) of measuring metastasis in an experimental setting. This AI-based algorithm, made freely available to academic laboratories through a web-interface called MetFinder, promises to become an asset for melanoma researchers and pathologists interested in accurate, quantitative assessment of metastasis burden.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA244107,PS-ON,"Microenvironment, Metastasis",10.1109/tmi.2024.3385644,IEEE Trans Med Imaging,38593022,https://pubmed.ncbi.nlm.nih.gov/38593022,Non-Invasive Imaging of Mechanical Properties of Cancers In Vivo Based on Transformations of the Eshelby's Tensor Using Compression Elastography,2024,,"Sharmin Majumder, Md Tauhidul Islam, Francesca Taraballi, Raffaella Righetti","Knowledge of the mechanical properties is of great clinical significance for diagnosis, prognosis and treatment of cancers. Recently, a new method based on Eshelby's theory to simultaneously assess Young's modulus (YM) and Poisson's ratio (PR) in tissues has been proposed. A significant limitation of this method is that accuracy of the reconstructed YM and PR is affected by the orientation/alignment of the tumor with the applied stress. In this paper, we propose a new method to reconstruct YM and PR in cancers that is invariant to the 3D orientation of the tumor with respect to the axis of applied stress. The novelty of the proposed method resides on the use of a tensor transformation to improve the robustness of Eshelby's theory and reconstruct YM and PR of tumors with high accuracy and in realistic experimental conditions. The method is validated using finite element simulations and controlled experiments using phantoms with known mechanical properties. The in vivo feasibility of the developed method is demonstrated in an orthotopic mouse model of breast cancer. Our results show that the proposed technique can estimate the YM and PR with overall accuracy of (97.06 ± 2.42) % under all tested tumor orientations. Animal experimental data demonstrate the potential of the proposed methodology in vivo. The proposed method can significantly expand the range of applicability of the Eshelby's theory to tumors and provide new means to accurately image and quantify mechanical parameters of cancers in clinical conditions.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,"CA284090, CA268083","CCBIR, MetNet","Microenvironment, Method/Assay Development, Metastasis, Tumor Progression",10.1083/jcb.202311002,J Cell Biol,39320351,https://pubmed.ncbi.nlm.nih.gov/39320351,Claudin 7 suppresses invasion and metastasis through repression of a smooth muscle actin program,2024,,"Junior J West, Rosela Golloshi, Chae Yun Cho, Yuqian Wang, Parker Stevenson, Genevieve Stein-O'Brien, Elana J Fertig, Andrew J Ewald","Metastasis initiates when cancer cells escape from the primary tumor, which requires changes to intercellular junctions. Claudins are transmembrane proteins that form the tight junction, and their expression is reduced in aggressive breast tumors. However, claudins' roles during breast cancer metastasis remain unclear. We used gain- and loss-of-function genetics in organoids isolated from murine breast cancer models to establish that Cldn7 suppresses invasion and metastasis. Transcriptomic analysis revealed that Cldn7 knockdown induced smooth muscle actin (SMA)-related genes and a broader mesenchymal phenotype. We validated our results in human cell lines, fresh human tumor tissue, bulk RNA-seq, and public single-cell RNA-seq data. We consistently observed an inverse relationship between Cldn7 expression and expression of SMA-related genes. Furthermore, knockdown and overexpression of SMA-related genes demonstrated that they promote breast cancer invasion. Our data reveal that Cldn7 suppresses breast cancer invasion and metastasis through negative regulation of SMA-related and mesenchymal gene expression.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA282451,TEC,"Microenvironment, Experimental Model Development",10.1126/science.adi1563,Science,38060634,https://pubmed.ncbi.nlm.nih.gov/38060634,Self-enhancing sono-inks enable deep-penetration acoustic volumetric printing,2023,,"Xiao Kuang, Qiangzhou Rong, Saud Belal, Tri Vu, Alice M López López, Nanchao Wang, Mehmet Onur Arıcan, Carlos Ezio Garciamendez-Mijares, Maomao Chen, Junjie Yao, Yu Shrike Zhang","Volumetric printing, an emerging additive manufacturing technique, builds objects with enhanced printing speed and surface quality by forgoing the stepwise ink-renewal step. Existing volumetric printing techniques almost exclusively rely on light energy to trigger photopolymerization in transparent inks, limiting material choices and build sizes. We report a self-enhancing sonicated ink (or sono-ink) design and corresponding focused-ultrasound writing technique for deep-penetration acoustic volumetric printing (DAVP). We used experiments and acoustic modeling to study the frequency and scanning rate-dependent acoustic printing behaviors. DAVP achieves the key features of low acoustic streaming, rapid sonothermal polymerization, and large printing depth, enabling the printing of volumetric hydrogels and nanocomposites with various shapes regardless of their optical properties. DAVP also allows printing at centimeter depths through biological tissues, paving the way toward minimally invasive medicine.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA227550,CSBC,"Heterogeneity, Drug Resistance/Sensitivity",10.1158/0008-5472.can-24-0086,Cancer Res,38330147,https://pubmed.ncbi.nlm.nih.gov/38330147,Fibroblasts in the Aged Pancreas Drive Pancreatic Cancer Progression,2024,,"Daniel J Zabransky, Yash Chhabra, Mitchell E Fane, Emma Kartalia, James M Leatherman, Laura Hüser, Jacquelyn W Zimmerman, Daniel Delitto, Song Han, Todd D Armstrong, Soren Charmsaz, Samantha Guinn, Sneha Pramod, Elizabeth D Thompson, Steven J Hughes, Jennifer O'Connell, Josephine M Egan, Elizabeth M Jaffee, Ashani T Weeraratna","Pancreatic cancer is more prevalent in older individuals and often carries a poorer prognosis for them. The relationship between the microenvironment and pancreatic cancer is multifactorial, and age-related changes in nonmalignant cells in the tumor microenvironment may play a key role in promoting cancer aggressiveness. Because fibroblasts have profound impacts on pancreatic cancer progression, we investigated whether age-related changes in pancreatic fibroblasts influence cancer growth and metastasis. Proteomics analysis revealed that aged fibroblasts secrete different factors than young fibroblasts, including increased growth/differentiation factor 15 (GDF-15). Treating young mice with GDF-15 enhanced tumor growth, whereas aged GDF-15 knockout mice showed reduced tumor growth. GDF-15 activated AKT, rendering tumors sensitive to AKT inhibition in an aged but not young microenvironment. These data provide evidence for how aging alters pancreatic fibroblasts and promotes tumor progression, providing potential therapeutic targets and avenues for studying pancreatic cancer while accounting for the effects of aging. Significance: Aged pancreatic fibroblasts secrete GDF-15 and activate AKT signaling to promote pancreatic cancer growth, highlighting the critical role of aging-mediated changes in the pancreatic cancer microenvironment in driving tumor progression. See related commentary by Isaacson et al., p. 1185.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA268083,CCBIR,"Microenvironment, Method/Assay Development, Metastasis",10.1158/0008-5472.can-23-3082,Cancer Res,38959339,https://pubmed.ncbi.nlm.nih.gov/38959339,E-Cadherin Induces Serine Synthesis to Support Progression and Metastasis of Breast Cancer,2024,,"Geonhui Lee, Claudia Wong, Anna Cho, Junior J West, Ashleigh J Crawford, Gabriella C Russo, Bishwa R Si, Jungwoo Kim, Lauren Hoffner, Cholsoon Jang, Moonjung Jung, Robert D Leone, Konstantinos Konstantopoulos, Andrew J Ewald, Denis Wirtz, Sangmoo Jeong","The loss of E-cadherin, an epithelial cell adhesion molecule, has been implicated in metastasis by mediating the epithelial-mesenchymal transition, which promotes invasion and migration of cancer cells. However, recent studies have demonstrated that E-cadherin supports the survival and proliferation of metastatic cancer cells. Here, we identified a metabolic role for E-cadherin in breast cancer by upregulating the de novo serine synthesis pathway (SSP). The upregulated SSP provided metabolic precursors for biosynthesis and resistance to oxidative stress, enabling E-cadherin+ breast cancer cells to achieve faster tumor growth and enhanced metastases. Inhibition of phosphoglycerate dehydrogenase, a rate-limiting enzyme in the SSP, significantly and specifically hampered proliferation of E-cadherin+ breast cancer cells and rendered them vulnerable to oxidative stress, inhibiting their metastatic potential. These findings reveal that E-cadherin reprograms cellular metabolism, promoting tumor growth and metastasis of breast cancers. Significance: E-Cadherin promotes the progression and metastasis of breast cancer by upregulating the de novo serine synthesis pathway, offering promising targets for inhibiting tumor growth and metastasis in E-cadherin-expressing tumors.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access +PublicationView,CA274506,CSBC,"Microenvironment, Tumor-Immune",10.1097/cmr.0000000000000974,Melanoma Res,38640504,https://pubmed.ncbi.nlm.nih.gov/38640504,Pseudoprogression in a patient with metastatic melanoma treated with PD-1 and LAG-3 inhibition,2024,,"Lawrence W Wu, Jacqueline J Tao, Diana McDonnell, Benjamin Izar","Pseudoprogression encapsulates a process of temporary radiographic growth followed by subsequent regression of metastatic melanoma lesions in response to immune checkpoint blockade (ICB), such as the combination of anti-programmed cell death protein 1 (PD-1) and anticytotoxic T-lymphocyte-associated antigen 4 therapy. This occurs in approximately 5-10% of ICB-treated patients, but has not yet been described in the context of novel combination therapies. Here, we report a case of an 89-year-old patient with metastatic melanoma to the liver, lung and lymph nodes, who underwent treatment with Opdualag (combining anti-PD-1 nivolumab and anti-lymphocyte-activation gene 3 relatlimab ICBs), and developed pseudoprogression after two cycles of therapy. The patient experienced a radiographic increase in liver metastatic lesion size, but was found to have a subsequent reduction in these lesions. The patient has been on therapy for 18 months without evidence of disease progression and continues to be clinically well-appearing.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access diff --git a/annotations/processing-splits.py b/annotations/processing-splits.py index 2e4ea25e..4386222b 100644 --- a/annotations/processing-splits.py +++ b/annotations/processing-splits.py @@ -23,7 +23,7 @@ def process_csv(file_path): # 2. Add "PublicationView_id" as a column if not present, and fill it with values from "Pubmed Id" column if "PublicationView_id" not in df.columns and "Pubmed Id" in df.columns: - df["PublicationView_id"] = df["Pubmed Id"] + df.insert(1,'PublicationView_id',df['Pubmed Id'].copy()) # 3. Drop 'Publication Theme Name' and 'Publication Consortium Name' columns columns_to_drop = ["Publication Theme Name", "Publication Consortium Name"] @@ -39,6 +39,12 @@ def process_csv(file_path): else x ) ) + # Re-order the Dataframe with columns in the same order as the union table + if "Publication Dataset Alias" in df.columns and "Publication Accessibility" in df.columns: + col_list = list(df.columns) + x,y = col_list.index('Publication Dataset Alias'), col_list.index('Publication Accessibility') + col_list[y], col_list[x] = col_list[x], col_list[y] + df = df[col_list] # Save the modified DataFrame back to the CSV file df.to_csv(file_path, index=False) diff --git a/annotations/split_manifest_grants.py b/annotations/split_manifest_grants.py old mode 100644 new mode 100755 diff --git a/annotations/upload-workflow.sh b/annotations/upload-workflow.sh old mode 100644 new mode 100755 index 9c8bf20a..11a1a94c --- a/annotations/upload-workflow.sh +++ b/annotations/upload-workflow.sh @@ -2,44 +2,56 @@ #Outlines workflow for curation processing and upload #author: aditi.gopalan +#Make sure to run this script from the root directory (~/)end + + # Activate the Conda environment -echo "Activating conda environment: schematic" -conda activate schematic +echo "Activating conda environment: schematic2" +conda init +conda activate schematic2 # Run python3 split_manifest_grants.py echo "Splitting manifests..." -python3 split_manifest_grants.py feb_manifest.csv publication ./output/output_feb --csv +python3 ~/Documents/code/mc2-center-dcc/annotations/split_manifest_grants.py ~/Documents/code/mc2-center-dcc/annotations/input/jan25_pubs.csv publication ~/Documents/code/mc2-center-dcc/annotations/output/output_jan25 --csv # Check if split_manifest_grants.py was successful if [ $? -eq 0 ]; then # Generate file paths for split manifests echo "Generating file paths..." - python3 gen-mp-csv.py ./output/output_feb feb_filepaths.csv publications + python3 ~/Documents/code/mc2-center-dcc/annotations/gen-mp-csv.py ~/Documents/code/mc2-center-dcc/annotations/output/output_nov ~/Documents/code/mc2-center-dcc/annotations/input/jan25_filepaths.csv publications # Check if file path generation was successful if [ $? -eq 0 ]; then # Format manifests echo "Processing split files..." - python3 processing-splits.py ./output/output_feb + python3 ~/Documents/code/mc2-center-dcc/annotations/processing-splits.py ~/Documents/code/mc2-center-dcc/annotations/output/output_jan25 # Check if formatting was successful if [ $? -eq 0 ]; then # Run schema updates, generating IDs echo "Running schema updates..." - python3 schema_update.py feb_filepaths.csv Publication + python3 ~/Documents/code/mc2-center-dcc/annotations/schema_update.py ~/Documents/code/mc2-center-dcc/annotations/input/jan25_filepaths.csv Publication - echo "Generating Dataset/ Tool/ Educational Resource folder Ids" - python3 create_id_folders.py -m april_datasets_filepaths.csv -t DatasetView + # echo "Generating Dataset/ Tool/ Educational Resource folder Ids" + # python3 create_id_folders.py -m nov_datasets_filepaths.csv -t DatasetView # Check if schema_update.py was successful if [ $? -eq 0 ]; then # Run python3 upload-manifests.py echo "Uploading manifests..." - python3 upload-manifests.py -m feb_filepaths.csv -t PublicationView -c /Users/agopalan/schematic/config.yml + python3 ~/Documents/code/mc2-center-dcc/annotations/upload-manifests.py -m ~/Documents/code/mc2-center-dcc/annotations/input/jan25_filepaths.csv -t PublicationView -c ~/config.yml - # Check if upload-manifests.py was successful if [ $? -eq 0 ]; then - echo "All scripts executed successfully." + # Run python3 upload-validation.py + echo "Validate Uploads..." + python3 ~/Documents/code/mc2-center-dcc/annotations/upload_validation.py ~/Documents/code/mc2-center-dcc/annotations/input/jan25_filepaths.csv Publication + + # Check if upload-manifests.py was successful + if [ $? -eq 0 ]; then + echo "All scripts executed successfully." + else + echo "Error: upload_validation.py failed." + fi else echo "Error: upload-manifests.py failed." fi @@ -54,7 +66,4 @@ if [ $? -eq 0 ]; then fi else echo "Error: split_manifest_grants.py failed." -fi -else - echo "Error: Conda environment activation failed." -fi +fi \ No newline at end of file From 520a8b99c35e8b5f23dc7fbf1fc5292ca24796a5 Mon Sep 17 00:00:00 2001 From: Aditya Nath Date: Fri, 14 Feb 2025 15:54:41 -0800 Subject: [PATCH 2/2] Issues with gitignore --- .gitignore | 1 + annotations/input/jan25_filepaths.csv | 5 --- annotations/input/jan25_pubs.csv | 31 -------------- annotations/input/nov_datasets.csv | 18 --------- annotations/input/nov_filepaths.csv | 45 --------------------- annotations/input/nov_pubs.csv | 48 ---------------------- annotations/oct_filepaths.csv | 50 ----------------------- annotations/oct_manifest.csv | 58 --------------------------- 8 files changed, 1 insertion(+), 255 deletions(-) delete mode 100644 annotations/input/jan25_filepaths.csv delete mode 100644 annotations/input/jan25_pubs.csv delete mode 100644 annotations/input/nov_datasets.csv delete mode 100644 annotations/input/nov_filepaths.csv delete mode 100644 annotations/input/nov_pubs.csv delete mode 100644 annotations/oct_filepaths.csv delete mode 100755 annotations/oct_manifest.csv diff --git a/.gitignore b/.gitignore index 9e00e65e..41a50ed2 100644 --- a/.gitignore +++ b/.gitignore @@ -134,6 +134,7 @@ dmypy.json great_expectations/ .vscode/ +inputs/ outputs/ upload_check* *manifests/ diff --git a/annotations/input/jan25_filepaths.csv b/annotations/input/jan25_filepaths.csv deleted file mode 100644 index 7daba32d..00000000 --- a/annotations/input/jan25_filepaths.csv +++ /dev/null @@ -1,5 +0,0 @@ -File Paths,folderIdPublication -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA245313_publication.csv,syn32698418 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA225088_publication.csv,syn32698012 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA282451_publication.csv,syn53212972 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA232216_publication.csv,syn32698110 diff --git a/annotations/input/jan25_pubs.csv b/annotations/input/jan25_pubs.csv deleted file mode 100644 index ca09a3bd..00000000 --- a/annotations/input/jan25_pubs.csv +++ /dev/null @@ -1,31 +0,0 @@ -Component,Publication Grant Number,Publication Consortium Name,Publication Theme Name,Publication Doi,Publication Journal,Pubmed Id,Pubmed Url,Publication Title,Publication Year,Publication Keywords,Publication Authors,Publication Abstract,Publication Assay,Publication Tumor Type,Publication Tissue,Publication Dataset Alias,Publication Accessibility -PublicationView,CA274502,CSBC,"Computational Resource, Heterogeneity",https://doi.org/10.1016/j.devcel.2024.11.021,Dev Cell,39706188,https://pubmed.ncbi.nlm.nih.gov/39706188,Global versus local matrix remodeling drives rotational versus invasive collective migration of epithelial cells,2024,"Matrix Metalloproteinase, adhesion, Mt1-mmp, Matrix Remodeling, Collective Migration, Adherens Junctions, Invasive Migration, Itgβ1, Rotational Migration","Sural K Ranamukhaarachchi, Alyssa Walker, Man-Ho Tang, William D Leineweber, Sophia Lam, Wouter-Jan Rappel, Stephanie I Fraley","The coordinated movement of cell collectives is essential for normal epithelial tissue development, maintenance, and cancer progression. Here, we report on a minimal 3D extracellular matrix (ECM) system wherein both invasive collective migration (ICM) and rotational collective migration (RCM) arise spontaneously from individually seeded epithelial cells of mammary and hepatic origin, regardless of whether they express adherens junctions, and lead to ductal-like and acinar-like structures, respectively. Quantitative microscopy and cellular Potts modeling reveal that initial differences in cell protrusion dynamics and matrix-remodeling localization generate RCM and ICM behavior in confining 3D ECM. Matrix-remodeling activity by matrix metalloproteinases (MMPs) is localized to the base of protrusions in cells that initiate ICM, whereas RCM does not require MMPs and is associated with ITGβ1-mediated remodeling localized globally around the cell body. Further analysis in vitro and in vivo supports the concept that distinct matrix-remodeling strategies encode collective migration behaviors and tissue structure.","Western Blotting, Fluorescence Imaging, Immunohistochemistry Staining Method",Pan-cancer,Not Applicable,,Open Access -PublicationView,CA253472,CSBC,"Tumor-Immune, Drug Resistance/Sensitivity",https://doi.org/10.1186/s13073-024-01393-6,Genome Med,39468667,https://pubmed.ncbi.nlm.nih.gov/39468667,Developmental-status-aware transcriptional decomposition establishes a cell state panorama of human cancers,2024,"Cell differentiation, organogenesis, Gene Expression, Stemness, Tcga, Pan-cancer, Scrna-seq, Prognostic And Predictive Biomarkers, Oncofetal Reprogramming, Transcriptional Decomposition","Yikai Luo, Han Liang","Background: Cancer cells evolve under unique functional adaptations that unlock transcriptional programs embedded in adult stem and progenitor-like cells for progression, metastasis, and therapeutic resistance. However, it remains challenging to quantify the stemness-aware cell state of a tumor based on its gene expression profile. Methods: We develop a developmental-status-aware transcriptional decomposition strategy using single-cell RNA-sequencing-derived tissue-specific fetal and adult cell signatures as anchors. We apply our method to various biological contexts, including developing human organs, adult human tissues, experimentally induced differentiation cultures, and bulk human tumors, to benchmark its performance and to reveal novel biology of entangled developmental signaling in oncogenic processes. Results: Our strategy successfully captures complex dynamics in developmental tissue bulks, reveals remarkable cellular heterogeneity in adult tissues, and resolves the ambiguity of cell identities in in vitro transformations. Applying it to large patient cohorts of bulk RNA-seq, we identify clinically relevant cell-of-origin patterns and observe that decomposed fetal cell signals significantly increase in tumors versus normal tissues and metastases versus primary tumors. Across cancer types, the inferred fetal-state strength outperforms published stemness indices in predicting patient survival and confers substantially improved predictive power for therapeutic responses. Conclusions: Our study not only provides a general approach to quantifying developmental-status-aware cell states of bulk samples but also constructs an information-rich, biologically interpretable, cell-state panorama of human cancers, enabling diverse translational applications.","RNA Sequencing, Mathematical Modeling",Pan-cancer,Not Applicable,,Open Access -PublicationView,CA261701,MetNet,"Tumor-Immune, Metastasis, Microenvironment",https://doi.org/10.1038/s41586-024-07767-5,Nature,39112700,https://pubmed.ncbi.nlm.nih.gov/39112700,Neuronal substance P drives metastasis through an extracellular RNA-TLR7 axis,2024,,"Veena Padmanaban, Isabel Keller, Ethan S Seltzer, Benjamin N Ostendorf, Zachary Kerner, Sohail F Tavazoie","Tumour innervation is associated with worse patient outcomes in multiple cancers1,2, which suggests that it may regulate metastasis. Here we observed that highly metastatic mouse mammary tumours acquired more innervation than did less-metastatic tumours. This enhanced innervation was driven by expression of the axon-guidance molecule SLIT2 in tumour vasculature. Breast cancer cells induced spontaneous calcium activity in sensory neurons and elicited release of the neuropeptide substance P (SP). Using three-dimensional co-cultures and in vivo models, we found that neuronal SP promoted breast tumour growth, invasion and metastasis. Moreover, patient tumours with elevated SP exhibited enhanced lymph node metastatic spread. SP acted on tumoral tachykinin receptors (TACR1) to drive death of a small population of TACR1high cancer cells. Single-stranded RNAs (ssRNAs) released from dying cells acted on neighbouring tumoural Toll-like receptor 7 (TLR7) to non-canonically activate a prometastatic gene expression program. This SP- and ssRNA-induced Tlr7 gene expression signature was associated with reduced breast cancer survival outcomes. Therapeutic targeting of this neuro-cancer axis with the TACR1 antagonist aprepitant, an approved anti-nausea drug, suppressed breast cancer growth and metastasis in multiple models. Our findings reveal that tumour-induced hyperactivation of sensory neurons regulates multiple aspects of metastatic progression in breast cancer through a therapeutically targetable neuropeptide/extracellular ssRNA sensing axis.","Murine Model, Viral Transduction, siRNA, Western Blotting, Fluorescence Imaging, qPCR, Flow Cytometry, RNA Sequencing",Breast Carcinoma,Breast,"SRX24613796, GSE267958, SRP508791, SRX24613794, SRX24613789, SRX24613792, SRX24613791, SRX24613795, SRX24613790, SRX24613793",Open Access -PublicationView,CA214297,PS-ON,"Metastasis, Microenvironment",https://doi.org/10.1038/s41467-024-55140-x,Nat Commun,39746954,https://pubmed.ncbi.nlm.nih.gov/39746954,Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product,2025,,"Avanish Mishra, Shih-Bo Huang, Taronish Dubash, Risa Burr, Jon F Edd, Ben S Wittner, Quinn E Cunneely, Victor R Putaturo, Akansha Deshpande, Ezgi Antmen, Kaustav A Gopinathan, Keisuke Otani, Yoshiyuki Miyazawa, Ji Eun Kwak, Sara Y Guay, Justin Kelly, John Walsh, Linda T Nieman, Isabella Galler, PuiYee Chan, Michael S Lawrence, Ryan J Sullivan, Aditya Bardia, Douglas S Micalizzi, Lecia V Sequist, Richard J Lee, Joseph W Franses, David T Ting, Patricia A R Brunker, Shyamala Maheswaran, David T Miyamoto, Daniel A Haber, Mehmet Toner","Circulating Tumor Cells (CTCs) in blood encompass DNA, RNA, and protein biomarkers, but clinical utility is limited by their rarity. To enable tumor epitope-agnostic interrogation of large blood volumes, we developed a high-throughput microfluidic device, depleting hematopoietic cells through high-flow channels and force-amplifying magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.83 liters from seven patients with metastatic cancer. High CTC yields (mean 10,057 CTCs per patient; range 100 to 58,125) reveal considerable intra-patient heterogeneity. CTC size varies within patients, with 67% overlapping in diameter with WBCs. Paired single-cell DNA and RNA sequencing identifies subclonal patterns of aneuploidy and distinct signaling pathways within CTCs. In prostate cancers, a subpopulation of small aneuploid cells lacking epithelial markers is enriched for neuroendocrine signatures. Pooling of CNV-confirmed CTCs enables whole exome sequencing with high mutant allele fractions. High-throughput CTC enrichment thus enables cell-based liquid biopsy for comprehensive monitoring of cancer.","RNA Sequencing, Droplet Digital PCR",Pan-Cancer,Not Applicable,,Open Access -PublicationView,CA210152,PS-ON,"Metastasis, Microenvironment",https://doi.org/10.1016/j.neo.2024.101036,Neoplasia,39173508,https://pubmed.ncbi.nlm.nih.gov/39173508,Characterization of circulating tumor cells in patients with metastatic bladder cancer utilizing functionalized microfluidics,2024,"EGFR, Differential gene expression, Bladder cancer, Her2, Cd31, Circulating Tumor Cells, Adam15, Targeted Transcriptome Sequencing, Graphene Oxide Microfluidic Chip","Zeqi Niu, Molly Kozminsky, Kathleen C Day, Luke J Broses, Marian L Henderson, Christopher Patsalis, Rebecca Tagett, Zhaoping Qin, Sarah Blumberg, Zachery R Reichert, Sofia D Merajver, Aaron M Udager, Phillip L Palmbos, Sunitha Nagrath, Mark L Day","Assessing the molecular profiles of bladder cancer (BC) from patients with locally advanced or metastatic disease provides valuable insights, such as identification of invasive markers, to guide personalized treatment. Currently, most molecular profiling of BC is based on highly invasive biopsy or transurethral tumor resection. Liquid biopsy takes advantage of less-invasive procedures to longitudinally profile disease. Circulating tumor cells (CTCs) isolated from blood are one of the key analytes of liquid biopsy. In this study, we developed a protein and mRNA co-analysis workflow for BC CTCs utilizing the graphene oxide (GO) microfluidic chip. The GO chip was conjugated with antibodies against both EpCAM and EGFR to isolate CTCs from 1 mL of blood drawn from BC patients. Following CTC capture, protein and mRNA were analyzed using immunofluorescent staining and ion-torrent-based whole transcriptome sequencing, respectively. Elevated CTC counts were significantly associated with patient disease status at the time of blood draw. We found a count greater than 2.5 CTCs per mL was associated with shorter overall survival. The invasive markers EGFR, HER2, CD31, and ADAM15 were detected in CTC subpopulations. Whole transcriptome sequencing showed distinct RNA expression profiles from patients with or without tumor burden at the time of blood draw. In patients with advanced metastatic disease, we found significant upregulation of metastasis-related and chemotherapy-resistant genes. This methodology demonstrates the capability of GO chip-based assays to identify tumor-related RNA signatures, highlighting the prognostic potential of CTCs in metastatic BC patients.","Fluorescence Imaging, Mathematical Modeling",Bladder Carcinoma,Bladder,,Open Access -PublicationView,CA268084,CCBIR,"Platform Development, Epigenetics, Computational Model Development",https://doi.org/10.3389/fnmol.2024.1484964,Front Mol Neurosci,39703720,https://pubmed.ncbi.nlm.nih.gov/39703720,Transcorneal electrical stimulation restores DNA methylation changes in retinal degeneration,2024,"Retina, DNA methylation, Electrical stimulation, epigenomics, Retinal degeneration","Ben Yi Tew, Gerald C Gooden, Pei-An Lo, Dimitrios Pollalis, Brandon Ebright, Alex J Kalfa, Alejandra Gonzalez-Calle, Biju Thomas, David N Buckley, Thomas Simon, Zeyi Yang, Ege Iseri, Cody L Dunton, Vadim Backman, Stan Louie, Gianluca Lazzi, Mark S Humayun, Bodour Salhia","Background: Retinal degeneration is a major cause of irreversible blindness. Stimulation with controlled low-level electrical fields, such as transcorneal electrical stimulation (TES), has recently been postulated as a therapeutic strategy. With promising results, there is a need for detailed molecular characterization of the therapeutic effects of TES. Methods: Controlled, non-invasive TES was delivered using a custom contact lens electrode to the retinas of Royal College of Surgeons (RCS) rats, a model of retinal degeneration. DNA methylation in the retina, brain and cell-free DNA in plasma was assessed by reduced representation bisulfite sequencing (RRBS) and gene expression by RNA sequencing. Results: TES induced DNA methylation and gene expression changes implicated in neuroprotection in the retina of RCS rats. We devised an epigenomic-based retinal health score, derived from DNA methylation changes observed with disease progression in RCS rats, and showed that TES improved the epigenomic health of the retina. TES also induced DNA methylation changes in the superior colliculus: the brain which is involved in integrating visual signaling. Lastly, we demonstrated that TES-induced retinal DNA methylation changes were detectable in cell-free DNA derived from plasma. Conclusion: TES induced DNA methylation changes with therapeutic effects, which can be measured in circulation. Based on these changes, we were able to devise a liquid biopsy biomarker for retinal health. These findings shed light on the therapeutic potential and molecular underpinnings of TES, and provide a foundation for the further development of TES to improve the retinal health of patients with degenerative eye diseases.","Murine Model, Bisulfite Sequencing, RNA Sequencing",Retinoblastoma,Eye,,Open Access -PublicationView,CA217617,PDMC,"Drug Resistance/Sensitivity, Experimental Model Development",https://doi.org/10.1016/j.xpro.2023.102402,STAR Protoc,37402170,https://pubmed.ncbi.nlm.nih.gov/37402170,Breast cancer PDxO cultures for drug discovery and functional precision oncology,2023,"Cancer, Cell culture, Organoids, Model Organisms, Cell-based Assays","Sandra D Scherer, Ling Zhao, Andrew J Butterfield, Chieh-Hsiang Yang, Emilio Cortes-Sanchez, Katrin P Guillen, Bryan E Welm, Alana L Welm","Patient-derived xenografts (PDXs) have clinical value but are time-, cost-, and labor-intensive and thus ill-suited for large-scale experiments. Here, we present a protocol to convert PDX tumors into PDxOs for long-term cultures amenable to moderate-throughput drug screens, including in-depth PDxO validation. We describe steps for PDxO preparation and mouse cell removal. We then detail PDxO validation and characterization and drug response assay. Our PDxO drug screening platform can predict therapy response in vivo and inform functional precision oncology for patients. For complete details on the use and execution of this protocol, please refer to Guillen et al.1.",Patient Derived Xenograft,Pan-cancer,Not Applicable,,Open Access -PublicationView,CA274499,CSBC,"Oncogenic Stress, Metabolism",https://doi.org/10.1186/s13058-024-01931-5,Breast Cancer Res,39741344,https://pubmed.ncbi.nlm.nih.gov/39741344,Patient-derived response estimates from zero-passage organoids of luminal breast cancer,2024,"Matrigel, Tamoxifen, systems biology, sulforaphane, Nqo1, Luminal, Organoid, Tp73","Róża K Przanowska, Najwa Labban, Piotr Przanowski, Russell B Hawes, Kristen A Atkins, Shayna L Showalter, Kevin A Janes","Background: Primary luminal breast cancer cells lose their identity rapidly in standard tissue culture, which is problematic for testing hormone interventions and molecular pathways specific to the luminal subtype. Breast cancer organoids are thought to retain tumor characteristics better, but long-term viability of luminal-subtype cases is a persistent challenge. Our goal was to adapt short-term organoids of luminal breast cancer for parallel testing of genetic and pharmacologic perturbations. Methods: We freshly isolated patient-derived cells from luminal tumor scrapes, miniaturized the organoid format into 5 µl replicates for increased throughput, and set an endpoint of 14 days to minimize drift. Therapeutic hormone targeting was mimicked in these ""zero-passage"" organoids by withdrawing β-estradiol and adding 4-hydroxytamoxifen. We also examined sulforaphane as an electrophilic stress and commercial nutraceutical with reported anti-cancer properties. Downstream mechanisms were tested genetically by lentiviral transduction of two complementary sgRNAs and Cas9 stabilization for the first week of organoid culture. Transcriptional changes were measured by RT-qPCR or RNA sequencing (RNA-seq), and organoid phenotypes were quantified by serial brightfield imaging, digital image segmentation, and regression modeling of volumetric growth rates. Results: We achieved > 50% success in initiating luminal breast cancer organoids from tumor scrapes and maintaining them to the 14-day zero-passage endpoint. Success was mostly independent of clinical parameters, supporting general applicability of the approach. Abundance of ESR1 and PGR in zero-passage organoids consistently remained within the range of patient variability at the endpoint. However, responsiveness to hormone withdrawal and blockade was highly variable among luminal breast cancer cases tested. Combining sulforaphane with knockout of NQO1 (a phase II antioxidant response gene and downstream effector of sulforaphane) also yielded a breadth of organoid growth phenotypes, including growth inhibition with sulforaphane, growth promotion with NQO1 knockout, and growth antagonism when combined. Conclusions: Zero-passage organoids are a rapid and scalable way to interrogate properties of luminal breast cancer cells from patient-derived material. This includes testing drug mechanisms of action in different clinical cohorts. A future goal is to relate inter-patient variability of zero-passage organoids to long-term outcomes.","RNA Sequencing, RT-qPCR, Viral Transduction, Western Blotting",Breast Carcinoma,Breast,,Open Access -PublicationView,CA268069,CCBIR,"Platform Development, Tumor-Immune, Immunotherapy, Microenvironment",https://doi.org/10.3390/ijms25094706,Int J Mol Sci,38731924,https://pubmed.ncbi.nlm.nih.gov/38731924,Implementation of FRET Spectrometry Using Temporally Resolved Fluorescence: A Feasibility Study,2024,"Protein quaternary structure, Fluorescence Lifetime Imaging Microscopy (Flim), Protein–protein Interactions, Förster Resonance Energy Transfer (Fret), Fret Spectrometry, Spectrally Resolved Fluorescence, Temporally Resolved Fluorescence","Justin Trujillo, Aliyah S Khan, Dhruba P Adhikari, Michael R Stoneman, Jenu V Chacko, Kevin W Eliceiri, Valerica Raicu","Förster resonance energy transfer (FRET) spectrometry is a method for determining the quaternary structure of protein oligomers from distributions of FRET efficiencies that are drawn from pixels of fluorescence images of cells expressing the proteins of interest. FRET spectrometry protocols currently rely on obtaining spectrally resolved fluorescence data from intensity-based experiments. Another imaging method, fluorescence lifetime imaging microscopy (FLIM), is a widely used alternative to compute FRET efficiencies for each pixel in an image from the reduction of the fluorescence lifetime of the donors caused by FRET. In FLIM studies of oligomers with different proportions of donors and acceptors, the donor lifetimes may be obtained by fitting the temporally resolved fluorescence decay data with a predetermined number of exponential decay curves. However, this requires knowledge of the number and the relative arrangement of the fluorescent proteins in the sample, which is precisely the goal of FRET spectrometry, thus creating a conundrum that has prevented users of FLIM instruments from performing FRET spectrometry. Here, we describe an attempt to implement FRET spectrometry on temporally resolved fluorescence microscopes by using an integration-based method of computing the FRET efficiency from fluorescence decay curves. This method, which we dubbed time-integrated FRET (or tiFRET), was tested on oligomeric fluorescent protein constructs expressed in the cytoplasm of living cells. The present results show that tiFRET is a promising way of implementing FRET spectrometry and suggest potential instrument adjustments for increasing accuracy and resolution in this kind of study.",Forster Resonance Energy Transfer,Pan-cancer,Not Applicable,,Open Access -PublicationView,CA248890,TEC,"Platform Development, Tumor Progression",https://doi.org/10.1039/d4lc00771a,Lab Chip,39659219,https://pubmed.ncbi.nlm.nih.gov/39659219,Retinal organoid chip: engineering a physiomimetic oxygen gradient for optimizing long term culture of human retinal organoids,2024,,"Emma Drabbe, Daniel Pelaez, Ashutosh Agarwal","An oxygen gradient across the retina plays a crucial role in its development and function. The inner retina resides in a hypoxic environment (2% O2) adjacent to the vitreous cavity. Oxygenation levels rapidly increase towards the outer retina (18% O2) at the choroid. In addition to retinal stratification, oxygen levels are critical for the health of retinal ganglion cells (RGCs), which relay visual information from the retina to the brain. Human stem cell derived retinal organoids are being engineered to mimic the structure and function of human retina for applications such as disease modeling, development of therapeutics, and cell replacement therapies. However, rapid degeneration of the retinal ganglion cell layers are a common limitation of human retinal organoid platforms. We report the design of a novel retinal organoid chip (ROC) that maintains a physiologically relevant oxygen gradient and allows the maturation of inner and outer retinal cell phenotypes for human retinal organoids. Our PDMS-free ROC holds 55 individual retinal organoids that were manually seeded, cultured for extended periods (over 150 days), imaged in situ, and retrieved. ROC was designed from first principles of liquid and gas mass transport, and fabricated from biologically- and chemically inert materials using rapid prototyping techniques such as micromachining, laser cutting, 3D printing and bonding. After computational and experimental validation of oxygen gradients, human induced pluripotent stem cell derived retinal organoids were transferred into the ROC, differentiated, cultured and imaged within the chip. ROCs that maintained active perfusion and stable oxygen gradients were successful in inducing higher viability of RGCs within retinal organoids than static controls, or ROC without oxygen gradients. Our physiologically relevant and higher-throughput retinal organoid culture system is well suited for applications in studying developmental perturbations to primate retinogenesis, including those driven by inherited traits, fetal environmental exposure to toxic agents, or acquired by genetic mutations, such as retinoblastoma.","Fluorescence Imaging, Organoid",Retinoblastoma,Eye,,Open Access -PublicationView,CA274502,CSBC,"Computational Resource, Heterogeneity",https://doi.org/10.1016/j.cell.2024.10.038,Cell,39547210,https://pubmed.ncbi.nlm.nih.gov/39547210,Discovery and significance of protein-protein interactions in health and disease,2024,,"Jack F Greenblatt, Bruce M Alberts, Nevan J Krogan","The identification of individual protein-protein interactions (PPIs) began more than 40 years ago, using protein affinity chromatography and antibody co-immunoprecipitation. As new technologies emerged, analysis of PPIs increased to a genome-wide scale with the introduction of intracellular tagging methods, affinity purification (AP) followed by mass spectrometry (MS), and co-fractionation MS (CF-MS). Now, combining the resulting catalogs of interactions with complementary methods, including crosslinking MS (XL-MS) and cryogenic electron microscopy (cryo-EM), helps distinguish direct interactions from indirect ones within the same or between different protein complexes. These powerful approaches and the promise of artificial intelligence applications like AlphaFold herald a future where PPIs and protein complexes, including energy-driven protein machines, will be understood in exquisite detail, unlocking new insights in the contexts of both basic biology and disease.",,Pan-cancer,Not Applicable,,Open Access -PublicationView,CA274502,CSBC,"Computational Resource, Heterogeneity",https://doi.org/10.1039/d4sm00971a,Soft Matter,39552222,https://pubmed.ncbi.nlm.nih.gov/39552222,Modeling collagen fibril degradation as a function of matrix microarchitecture,2024,,"Bhanjan Debnath, Badri Narayanan Narasimhan, Stephanie I Fraley, Padmini Rangamani","Collagenolytic degradation is a process fundamental to tissue remodeling. The microarchitecture of collagen fibril networks changes during development, aging, and disease. Such changes to microarchitecture are often accompanied by changes in matrix degradability. In a matrix, the pore size and fibril characteristics such as length, diameter, number, orientation, and curvature are the major variables that define the microarchitecture. In vitro, collagen matrices of the same concentration but different microarchitectures also vary in degradation rate. How do different microarchitectures affect matrix degradation? To answer this question, we developed a computational model of collagen degradation. We first developed a lattice model that describes collagen degradation at the scale of a single fibril. We then extended this model to investigate the role of microarchitecture using Brownian dynamics simulation of enzymes in a multi-fibril three dimensional matrix to predict its degradability. Our simulations predict that the distribution of enzymes around the fibrils is non-uniform and depends on the microarchitecture of the matrix. This non-uniformity in enzyme distribution can lead to different extents of degradability for matrices of different microarchitectures. Our simulations predict that for the same enzyme concentration and collagen concentration, a matrix with thicker fibrils degrades more than that with thinner fibrils. Our model predictions were tested using in vitro experiments with synthetic collagen gels of different microarchitectures. Experiments showed that indeed degradation of collagen depends on the matrix architecture and fibril thickness. In summary, our study shows that the microarchitecture of the collagen matrix is an important determinant of its degradability.",,,,,Restricted Access -PublicationView,CA243072,CSBC,Drug Resistance/Sensitivity,https://doi.org/10.1038/s41375-024-02493-3,Leukemia,39681640,https://pubmed.ncbi.nlm.nih.gov/39681640,Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia,2024,,"Tommaso Balestra, Lisa M Niswander, Asen Bagashev, Joseph P Loftus, Savannah L Ross, Robert K Chen, Samantha M McClellan, Jacob J Junco, Diego A Bárcenas López, Karen R Rabin, Terry J Fry, Sarah K Tasian","CRLF2 rearrangements occur in >50% of Ph-like and Down syndrome (DS)-associated B-acute lymphoblastic leukemia (ALL) and induce constitutive kinase signaling targetable by the JAK1/2 inhibitor ruxolitinib under current clinical investigation. While chimeric antigen receptor T cell (CART) immunotherapies have achieved remarkable remission rates in children with relapsed/refractory B-ALL, ~50% of CD19CART-treated patients relapse again, many with CD19 antigen loss. We previously reported preclinical activity of thymic stromal lymphopoietin receptor-targeted cellular immunotherapy (TSLPRCART) against CRLF2-overexpressing ALL as an alternative approach. In this study, we posited that combinatorial TSLPRCART and ruxolitinib would have superior activity and first validated potent TSLPRCART-induced inhibition of leukemia proliferation in vitro in CRLF2-rearranged ALL cell lines and in vivo in Ph-like and DS-ALL patient-derived xenograft (PDX) models. However, simultaneous TSLPRCART/ruxolitinib or CD19CART/ruxolitinib treatment during initial CART expansion diminished T cell proliferation, blunted cytokine production, and/or facilitated leukemia relapse, which was abrogated by time-sequenced/delayed ruxolitinib co-exposure. Importantly, ruxolitinib co-administration prevented fatal TSLPRCART cytokine-associated toxicity in ALL PDX mice. Upon ruxolitinib withdrawal, TSLPRCART functionality recovered in vivo with clearance of subsequent ALL rechallenge. These translational studies demonstrate an effective two-pronged therapeutic strategy that mitigates acute CART-induced hyperinflammation and provides potential anti-leukemia 'maintenance' relapse prevention for CRLF2-rearranged Ph-like and DS-ALL.","Flow Cytometry, Xenograft",Leukemia,Blood,,Open Access -PublicationView,CA261719,MetNet,"Tumor-Immune, Metastasis, Microenvironment, Computational Model Development",https://doi.org/10.1126/science.adh8697,Science,38815010,https://pubmed.ncbi.nlm.nih.gov/38815010,Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity,2024,,"Kathleen E Houlahan, Aziz Khan, Noah F Greenwald, Cristina Sotomayor Vivas, Robert B West, Michael Angelo, Christina Curtis","Tumors with the same diagnosis can have different molecular profiles and response to treatment. It remains unclear when and why these differences arise. Somatic genomic aberrations occur within the context of a highly variable germline genome. Interrogating 5870 breast cancer lesions, we demonstrated that germline-derived epitopes in recurrently amplified genes influence somatic evolution by mediating immunoediting. Individuals with a high germline-epitope burden in human epidermal growth factor receptor 2 (HER2/ERBB2) are less likely to develop HER2-positive breast cancer compared with other subtypes. The same holds true for recurrent amplicons defining three aggressive estrogen receptor (ER)-positive subgroups. Tumors that overcome such immune-mediated negative selection are more aggressive and demonstrate an ""immune cold"" phenotype. These data show that the germline genome plays a role in dictating somatic evolution.",RNA Sequencing,Breast Carcinoma,Breast,,Open Access -PublicationView,CA209975,CSBC,"Metastasis, Tumor-Immune, Drug Resistance/Sensitivity, Microenvironment",https://doi.org/10.1038/s41586-024-08150-0,Nature,39478232,https://pubmed.ncbi.nlm.nih.gov/39478232,Progressive plasticity during colorectal cancer metastasis,2024,,"A R Moorman, E K Benitez, F Cambuli, Q Jiang, A Mahmoud, M Lumish, S Hartner, S Balkaran, J Bermeo, S Asawa, C Firat, A Saxena, F Wu, A Luthra, C Burdziak, Y Xie, V Sgambati, K Luckett, Y Li, Z Yi, I Masilionis, K Soares, E Pappou, R Yaeger, P Kingham, W Jarnagin, P Paty, M R Weiser, L Mazutis, M D'Angelica, J Shia, J Garcia-Aguilar, T Nawy, T J Hollmann, R Chaligné, F Sanchez-Vega, R Sharma, D Pe'er, K Ganesh","As cancers progress, they become increasingly aggressive-metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death1,2. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance3-5. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1 as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1 licenses non-canonical reprogramming.","Single Cell RNA-Sequencing, Mathematical Modeling",Pan-cancer,Not Applicable,,Open Access -PublicationView,CA214282,PS-ON,"Evolution, Heterogeneity",https://doi.org/10.1091/mbc.e24-04-0188,Mol Biol Cell,39292916,https://pubmed.ncbi.nlm.nih.gov/39292916,RAD51 regulates eukaryotic chromatin motions in the absence of DNA damage,2024,,"Amine Maarouf, Fadil Iqbal, Sarvath Sanaullah, Maëlle Locatelli, Andrew T Atanasiu, Daniel Kolbin, Chloé Hommais, Joëlle K Mühlemann, Keith Bonin, Kerry Bloom, Jing Liu, Pierre-Alexandre Vidi","In yeasts and higher eukaryotes, chromatin motions may be tuned to genomic functions, with transcriptional activation and the DNA damage response both leading to profound changes in chromatin dynamics. The RAD51 recombinase is a key mediator of chromatin mobility following DNA damage. As functions of RAD51 beyond DNA repair are being discovered, we asked whether RAD51 modulates chromatin dynamics in the absence of DNA damage and found that inhibition or depletion of RAD51 alters chromatin motions in undamaged cells. Inhibition of RAD51 increased nucleosome clustering. Predictions from polymer models are that chromatin clusters reduce chain mobility and, indeed, we measured reduced motion of individual chromatin loci in cells treated with a RAD51 inhibitor. This effect was conserved in mammalian cells, yeasts, and plant cells. In contrast, RAD51 depletion or inhibition increased global chromatin motions at the microscale. The results uncover a role for RAD51 in regulating local and global chromatin dynamics independently from DNA damage and highlight the importance of considering different physical scales when studying chromatin dynamics.","Fluorescence Imaging, Western Blotting, Cell Viability Assay",Pan-cancer,Not Applicable,,Open Access -PublicationView,CA274492,CSBC,"Tumor-Immune, Immunotherapy, Computational Model Development",https://doi.org/10.1038/s41467-024-55287-7,Nat Commun,39746987,https://pubmed.ncbi.nlm.nih.gov/39746987,A Bayesian active learning platform for scalable combination drug screens,2025,,"Christopher Tosh, Mauricio Tec, Jessica B White, Jeffrey F Quinn, Glorymar Ibanez Sanchez, Paul Calder, Andrew L Kung, Filemon S Dela Cruz, Wesley Tansey","Large-scale combination drug screens are generally considered intractable due to the immense number of possible combinations. Existing approaches use ad hoc fixed experimental designs then train machine learning models to impute unobserved combinations. Here we propose BATCHIE, an orthogonal approach that conducts experiments dynamically in batches. BATCHIE uses information theory and probabilistic modeling to design each batch to be maximally informative based on the results of previous experiments. On retrospective experiments from previous large-scale screens, BATCHIE designs rapidly discover highly effective and synergistic combinations. In a prospective combination screen of a library of 206 drugs on a collection of pediatric cancer cell lines, the BATCHIE model accurately predicts unseen combinations and detects synergies after exploring only 4% of the 1.4M possible experiments. Further, the model identifies a panel of top combinations for Ewing sarcomas, which follow-up validation experiments confirm to be effective, including the rational and translatable top hit of PARP plus topoisomerase I inhibition. These results demonstrate that adaptive experiments can enable large-scale unbiased combination drug screens with a relatively small number of experiments. BATCHIE is open source and publicly available ( https://github.com/tansey-lab/batchie ).","Mathematical Modeling, Artificial Intelligence",Pan-cancer,Not Applicable,,Open Access -PublicationView,CA268069,CCBIR,"Platform Development, Tumor-Immune, Immunotherapy, Microenvironment",https://doi.org/10.1242/jcs.262322,J Cell Sci,39475207,https://pubmed.ncbi.nlm.nih.gov/39475207,The crucial role of bioimage analysts in scientific research and publication,2024,"Training, Bioimaging, Bioimage Analysis, Bioimage Analysts","Beth A Cimini, Peter Bankhead, Rocco D'Antuono, Elnaz Fazeli, Julia Fernandez-Rodriguez, Caterina Fuster-Barceló, Robert Haase, Helena Klara Jambor, Martin L Jones, Florian Jug, Anna H Klemm, Anna Kreshuk, Stefania Marcotti, Gabriel G Martins, Sara McArdle, Kota Miura, Arrate Muñoz-Barrutia, Laura C Murphy, Michael S Nelson, Simon F Nørrelykke, Perrine Paul-Gilloteaux, Thomas Pengo, Joanna W Pylvänäinen, Lior Pytowski, Arianna Ravera, Annika Reinke, Yousr Rekik, Caterina Strambio-De-Castillia, Daniel Thédié, Virginie Uhlmann, Oliver Umney, Laura Wiggins, Kevin W Eliceiri","Bioimage analysis (BIA), a crucial discipline in biological research, overcomes the limitations of subjective analysis in microscopy through the creation and application of quantitative and reproducible methods. The establishment of dedicated BIA support within academic institutions is vital to improving research quality and efficiency and can significantly advance scientific discovery. However, a lack of training resources, limited career paths and insufficient recognition of the contributions made by bioimage analysts prevent the full realization of this potential. This Perspective - the result of the recent The Company of Biologists Workshop 'Effectively Communicating Bioimage Analysis', which aimed to summarize the global BIA landscape, categorize obstacles and offer possible solutions - proposes strategies to bring about a cultural shift towards recognizing the value of BIA by standardizing tools, improving training and encouraging formal credit for contributions. We also advocate for increased funding, standardized practices and enhanced collaboration, and we conclude with a call to action for all stakeholders to join efforts in advancing BIA.","Imaging, Mathematical Modeling",Pan-cancer,Not Applicable,,Open Access -PublicationView,CA217376,CSBC,"Evolution, Epigenetics, Heterogeneity, Microenvironment",https://doi.org/10.1016/j.ccell.2021.09.002,Cancer Cell,34597592,https://pubmed.ncbi.nlm.nih.gov/34597592,Evolution's cartographer: Mapping the fitness landscape in cancer,2021,,"Calum Gabbutt, Trevor A Graham","Cancer treatment effectiveness could be improved if it were possible to accurately anticipate the response of the tumor to treatment. Writing in Nature, Salehi et al. combine single-cell genomics and mathematical modeling to measure cancer subclone fitness and use these measurements to accurately predict the future trajectory of cancer evolution.",Mathematical Modeling,Pan-cancer,Not Applicable,,Open Access -PublicationView,CA224012,PDMC,"Drug Resistance/Sensitivity, Heterogeneity, Experimental Model Development",https://doi.org/10.1080/15384047.2024.2421584,Cancer Biol Ther,39513592,https://pubmed.ncbi.nlm.nih.gov/39513592,The polymeric fluoropyrimidine CF10 overcomes limitations of 5-FU in pancreatic ductal adenocarcinoma cells through increased replication stress,2024,"DNA damage, Pancreatic cancer, Fluoropyrimidine, Replication Stress, Pdac","Jennifer M Finan, Roberto Di Niro, Soon Young Park, Kang Jin Jeong, Madeline D Hedberg, Alexander Smith, Grace A McCarthy, Alex O Haber, John Muschler, Rosalie C Sears, Gordon B Mills, William H Gmeiner, Jonathan R Brody","Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease soon to become the second leading cause of cancer deaths in the US. Beside surgery, current therapies have narrow clinical benefits with systemic toxicities. FOLFIRINOX is the current standard of care, one component of which is 5- Fluorouracil (5-FU), which causes serious gastrointestinal and hematopoietic toxicities and is vulnerable to resistance mechanisms. Recently, we have developed polymeric fluoropyrimidines (F10, CF10) which unlike 5-FU, are, in principle, completely converted to the thymidylate synthase inhibitory metabolite FdUMP, without generating appreciable levels of ribonucleotides that cause systemic toxicities while displaying much stronger anti-cancer activity. Here, we confirm the potency of CF10 and investigate enhancement of its efficacy through combination with inhibitors in vitro targeting replication stress, a hallmark of PDAC cells. CF10 is 308-times more potent as a single agent than 5-FU and was effective in the nM range in primary patient derived models. Further, we find that activity of CF10, but not 5-FU, is enhanced through combination with inhibitors of ATR and Wee1 that regulate the S and G2 DNA damage checkpoints and can be reversed by addition of dNTPs indicative of CF10 acting, at least in part, through inducing replication stress. Our results indicate CF10 has the potential to supersede the established benefit of 5-FU in PDAC treatment and indicate novel combination approaches that should be validated in vivo and may be beneficial in established regimens that include 5-FU.","Western Blotting, Cell Viability Assay",Pancreatic Ductal Adenocarcinoma,Pancreas,,Open Access -PublicationView,CA223976,PDMC,"Microenvironment, Experimental Model Development",https://doi.org/10.3390/cells13231995,Cells,39682742,https://pubmed.ncbi.nlm.nih.gov/39682742,A High-Throughput Neurosphere-Based Colony Formation Assay to Test Drug and Radiation Sensitivity of Different Patient-Derived Glioblastoma Lines,2024,"Colony formation assay, Glioblastoma, Radiation Sensitivity, Clonogenic Assay, Brain Tumor Initiating Cells, Patient-derived Cancer Cells","Manoj Kumar, Lauren C Nassour-Caswell, Hasan Alrefai, Joshua C Anderson, Taylor L Schanel, Patricia H Hicks, Rex Cardan, Christopher D Willey","The gold standard assay for radiation response is the clonogenic assay, a normalized colony formation assay (CFA) that can capture a broad range of radiation-induced cell death mechanisms. Traditionally, this assay relies on two-dimensional (2D) cell culture conditions with colonies counted by fixing and staining protocols. While some groups have converted these to three-dimensional (3D) conditions, these models still utilize 2D-like media compositions containing serum that are incompatible with stem-like cell models such as brain tumor initiating cells (BTICs) that form self-aggregating spheroids in neural stem cell media. BTICs are the preferred patient-derived model system for studying glioblastoma (GBM) as they tend to better retain molecular and phenotypic characteristics of the original tumor tissue. As such, it is important that preclinical radiation studies should be adapted to BTIC conditions. In this study, we describe a series of experimental approaches for performing CFA experiments with BTIC cultures. Our results indicate that serum-free clonogenic assays are feasible for combination drug and radiation testing and may better facilitate translatability of preclinical findings.",Viral Transduction,Glioblastoma,Brain,,Open Access -PublicationView,CA217376,CSBC,"Evolution, Epigenetics, Heterogeneity, Microenvironment",https://doi.org/10.1038/s41568-024-00734-2,Nat Rev Cancer,39256635,https://pubmed.ncbi.nlm.nih.gov/39256635,The evolutionary theory of cancer: challenges and potential solutions,2024,,"Lucie Laplane, Carlo C Maley","The clonal evolution model of cancer was developed in the 1950s-1970s and became central to cancer biology in the twenty-first century, largely through studies of cancer genetics. Although it has proven its worth, its structure has been challenged by observations of phenotypic plasticity, non-genetic forms of inheritance, non-genetic determinants of clone fitness and non-tree-like transmission of genes. There is even confusion about the definition of a clone, which we aim to resolve. The performance and value of the clonal evolution model depends on the empirical extent to which evolutionary processes are involved in cancer, and on its theoretical ability to account for those evolutionary processes. Here, we identify limits in the theoretical performance of the clonal evolution model and provide solutions to overcome those limits. Although we do not claim that clonal evolution can explain everything about cancer, we show how many of the complexities that have been identified in the dynamics of cancer can be integrated into the model to improve our current understanding of cancer.",Mathematical Modeling,Pan-cancer,Not Applicable,,Open Access -PublicationView,CA209992,CSBC,"Metastasis, Microenvironment",https://doi.org/10.1038/s41467-024-53228-y,Nat Commun,39523366,https://pubmed.ncbi.nlm.nih.gov/39523366,Mechanical power is maximized during contractile ring-like formation in a biomimetic dividing cell model,2024,,"Ryota Sakamoto, Michael P Murrell","The spatial and temporal dynamics of forces in cells coordinate essential behaviors like division, polarization, and migration. While intracellular signaling initiates contractile ring assembly during cell division, how mechanical forces coordinate division and their energetic costs remain unclear. Here, we develop an in vitro model where myosin-induced stress drives division-like shape changes in giant unilamellar vesicles (GUVs, liposomes). Myosin activity is controlled by light patterns globally or locally at the equator. Global activation causes slow, shallow cleavage furrows due to a tug-of-war between the equatorial and polar forces. By contrast, local activation leads to faster, deeper, and symmetric division as equatorial forces dominate. Dissociating the actin cortex at the poles is crucial for inducing significant furrowing. During furrowing, actomyosin flows align actin filaments parallel to the division plane, forming a contractile ring-like structure. Mechanical power is not greatest during contraction, but is maximized just before furrowing. This study reveals the quantitative relationship between force patterning and mechanical energy during division-like shape changes, providing insights into cell division mechanics.","Fluorescence Imaging, Mathematical Modeling",Pan-cancer,Not Applicable,,Open Access -PublicationView,CA268069,CCBIR,"Platform Development, Tumor-Immune, Immunotherapy, Microenvironment",https://doi.org/10.1016/j.adro.2024.101677,Adv Radiat Oncol,39703718,https://pubmed.ncbi.nlm.nih.gov/39703718,Effect of External Beam Radiation Therapy and Brachytherapy on Circulating Myeloid-Derived Suppressor Cell Populations in Patients Treated Definitively for Cervical Cancer,2025,,"Kelsey M Wanhainen, Matthew Berkseth, Nicole Sando, Lydia Golden, Amy Techam, Jennifer Wieworka, Kyra M Boorsma Bergerud, Peter Argenta, Andrea O'Shea, Britt K Erickson, Sally Mullany, Colleen Rivard, Rahel Ghebre, Deanna Teoh, Margaret Reynolds, Stephanie Terezakis, Jianling Yuan, Lindsey Sloan","Purpose: The immunosuppressive function of myeloid-derived suppressor cells (MDSCs) has been implicated in the regulation of immune responses against cancer and is associated with poor prognosis. Radiation treatment is known to alter immune cell populations within the tumor; however, whether this results in the recruitment of immunosuppressive MDSC populations is not well understood. Here we evaluate the response of circulating MDSC populations in patients treated per standard-of-care cisplatin chemoradiation therapy (CRT) for locally invasive cervical cancer. Methods and materials: Newly diagnosed, treatment-naïve patients with locally advanced cervical cancer were enrolled. Blood samples were collected from patients prior to starting CRT (T0), after external beam radiation therapy (T1), and after high-dose-rate brachytherapy (T2). Samples from each time point were processed, and the prevalence of MDSC subsets was determined using flow cytometry. MDSC populations were identified using Live/Dead-CD11b+CD33+HLA-DR- staining. MDSC subsets were further subdivided into granulocytic (g-, CD15+CD14-), monocytic (m-, CD15-CD14+), or early-MDSCs (e-, CD15-CD14-). Results: Most patients in our study were Caucasian nonsmokers with human papillomavirus-associated squamous cell carcinoma of the cervix. We saw a trend for increased MDSC frequency in patients with more advanced-stage disease at the time of initiating treatment. MDSCs increase in response to CRT and peak after brachytherapy (T2). In particular, the g-MDSC subset increases by 6.44 times relative to the baseline. There was no correlation between MDSC expansion and response to therapy. Conclusion: Our study confirms other reports that circulating MDSCs in patients with cervical cancer increase in response to CRT and are associated with more advanced stages. Additionally, we show that MDSC expansion is driven by the g-MDSC subset. We did not see any correlation between MDSC expansion and treatment response, though this may be because of the limited sample size for this study.",Clinical Study,Cervical Carcinoma,Cervix Uteri,,Open Access -PublicationView,CA210152,PS-ON,"Metastasis, Microenvironment",https://doi.org/10.1172/jci170953,J Clin Invest,39480488,https://pubmed.ncbi.nlm.nih.gov/39480488,Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels,2024,"Bone marrow, Breast cancer, Bioinformatics, Oncology","Saptarshi Sinha, Brennan W Callow, Alex P Farfel, Suchismita Roy, Siyi Chen, Maria Masotti, Shrila Rajendran, Johanna M Buschhaus, Celia R Espinoza, Kathryn E Luker, Pradipta Ghosh, Gary D Luker","Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between ""borrowed"" and ""intrinsic"" components. Bioinformatics prioritized one of the borrowed components, CCDC88A/GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced approximately 20% of both the borrowed and the intrinsic gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.","RNA Sequencing, Murine Model",Breast Carcinoma,Breast,,Open Access -PublicationView,CA223976,PDMC,"Microenvironment, Experimental Model Development",https://doi.org/10.1016/j.radonc.2024.110646,Radiother Oncol,39579870,https://pubmed.ncbi.nlm.nih.gov/39579870,Altering fractionation during radiation overcomes radio-resistance in patient-derived glioblastoma cells assessed using a novel longitudinal radiation cytotoxicity assay,2025,"Cell viability, Radiosensitivity, Glioblastoma, xenograft, Btic","Lauren C Nassour-Caswell, Manoj Kumar, Christian T Stackhouse, Hasan Alrefai, Taylor L Schanel, Benjamin M Honan, Andee M Beierle, Patricia H Hicks, Joshua C Anderson, Christopher D Willey, Jeffrey S Peacock","Purpose: Current radiotherapy (RT) in glioblastoma (GBM) is delivered as constant dose fractions (CDF), which do not account for intratumoral-heterogeneity and radio-selection in GBM. These factors contribute to differential treatment response complicating the therapeutic efficacy of this principle. Our study aims to investigate an alternative dosing strategy to overcome radio-resistance using a novel longitudinal radiation cytotoxicity assay. Methods: Theoretical In-silico mathematical assumptions were combined with an in-vitro experimental strategy to investigate alternative radiation regimens. Patient-derived xenograft (PDX) brain tumor-initiating cells (BTICs) with differential radiation-sensitivities were tested individually with sham control and three regimens of the same nominal and average dose of 16 Gy (over four fractions), but with altered doses per fraction. Fractions were delivered conventionally (CDF: 4, 4, 4, 4 Gy), or as dynamic dose fractions (DDF) ""ramped down"" (RD: 7, 5, 3, 1 Gy), or DDF ""ramped up"" (RU: 1, 3, 5, 7 Gy), every 4 days. Interfraction-longitudinal data were collected by imaging cells every 5 days, and endpoint viability was taken on day 20. Results: The proposed method of radiosensitivity assessment allows for longitudinal-interfraction investigation in addition to endpoint analysis. Delivering four-fraction doses in an RD manner proves to be most effective at overcoming acquired radiation resistance in BTICs (Relative cell viability: CDF vs. RD: P < 0.0001; Surviving fraction: CDF: vs. RD: P < 0.0001). Conclusions: Using in-silico cytotoxicity prediction modeling and an altered radiosensitivity assessment, we show DDF-RD is effective at inducing cytotoxicity in three BTIC lines with differential radiosensitivity.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,"CA245313, CA274509, CA268083","CSBC, TEC, CCBIR","Method/Assay Development, Immunotherapy, Metastasis, Microenvironment, Drug Resistance/Sensitivity, Computational Model Development",https://doi.org/10.1038/s41592-024-02533-x,Nat Methods,39643677,https://pubmed.ncbi.nlm.nih.gov/39643677,Integrative spatial protein profiling with multi-omics,2024,,Rong Fan,No abstract available.,Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA209891,CSBC,"Evolution, Drug Resistance/Sensitivity, Heterogeneity",https://doi.org/10.1158/0008-5472.can-24-0456,Cancer Res,39652575,https://pubmed.ncbi.nlm.nih.gov/39652575,HBV Remodels PP2A Complexes to Rewire Kinase Signaling in Hepatocellular Carcinoma,2024,,"Rigney E Turnham, Adriana Pitea, Gwendolyn M Jang, Zhong Xu, Huat Chye Lim, Alex L Choi, John Von Dollen, Rebecca S Levin, James T Webber, Elizabeth McCarthy, Junjie Hu, Xiaolei Li, Li Che, Ananya Singh, Alex Yoon, Gary Chan, Robin K Kelley, Danielle L Swaney, Wei Zhang, Sourav Bandyopadhyay, Fabian J Theis, Manon Eckhardt, Xin Chen, Kevan M Shokat, Trey Ideker, Nevan J Krogan, John D Gordan","Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite the primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in HCC, suggesting that it impacts the biology of established HCC. Characterization of the interaction of HBV with host proteins and the mechanistic contributions of HBV to HCC initiation and maintenance could provide insights into HCC biology and uncover therapeutic vulnerabilities. Here, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human proteins in hepatocellular carcinoma (HCC). A subset of the host factors targeted by HBV proteins were preferentially mutated in non-HBV-associated HCC, suggesting that their interaction with HBV influences HCC biology. HBV interacted with proteins involved in mRNA splicing, mitogenic signaling, and DNA repair, with the latter set interacting with the HBV oncoprotein X (HBx). HBx remodeled the PP2A phosphatase complex by excluding striatin regulatory subunits from the PP2A holoenzyme, and the HBx effects on PP2A caused Hippo kinase activation. In parallel, HBx activated mTOR complex 2 (mTORC2), which can prevent YAP degradation. mTORC2-mediated upregulation of YAP was observed in human HCC specimens and mouse HCC models and could be targeted with mTOR kinase inhibitors. Thus, HBV interaction with host proteins rewires HCC signaling rather than directly activating mitogenic pathways, provide an alternative paradigm for the cellular effects of a tumor promoting virus.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,"CA250481, CA220378","PS-ON, CSBC","Evolution, Tumor-Immune, Heterogeneity",https://doi.org/10.1148/radiol.232555,Radiology,39656118,https://pubmed.ncbi.nlm.nih.gov/39656118,The QIBA Profile for Dynamic Susceptibility Contrast MRI Quantitative Imaging Biomarkers for Assessing Gliomas,2024,,"Mark S Shiroishi, Bradley J Erickson, Leland S Hu, Daniel P Barboriak, Lino Becerra, Laura C Bell, Michael A Boss, Jerrold L Boxerman, Steven Cen, Lisa Cimino, Zhaoyang Fan, Kathryn E Keenan, John E Kirsch, Nima Ameli, Sina Nazemi, C Chad Quarles, Mark A Rosen, Luis Rodriguez, Kathleen M Schmainda, Gudrun Zahlmann, Yuxiang Zhou, Nancy Obuchowski, Ona Wu, None None","The dynamic susceptibility contrast (DSC) MRI measures of relative cerebral blood volume (rCBV) play a central role in monitoring therapeutic response and disease progression in patients with gliomas. Previous investigations have demonstrated promise of using rCBV in classifying tumor grade, elucidating tumor viability after therapy, and differentiating pseudoprogression and pseudoresponse. However, the quantification and reproducibility of rCBV measurements across patients, devices, and software remain a critical barrier to routine or clinical trial use of longitudinal DSC MRI in patients with gliomas. To address this limitation, the RSNA DSC MRI Biomarker Committee of the Quantitative Imaging Biomarkers Alliance developed a Profile that defines statistics-based claims for the precision of longitudinal measurements. Although rCBV is the clinical marker of interest, the Profile focused on the reproducibility of the measured quantitative imaging biomarker, which is the area under the contrast agent concentration-time curve (AUC) normalized by the mean value of normal-appearing contralateral white matter tissue (tissue-normalized AUC values). Based on previous reports of within-subject coefficient of variation (wCV) in the tissue-normalized AUC values for enhancing gliomas (wCV = 0.31), an increase of 182% or more with respect to the baseline tissue-normalized AUC value indicates that an increase has occurred with 95% confidence. In contrast, a decrease of 64% or more with respect to baseline suggests that a decrease has occurred with 95% confidence. Similarly, an increase of 399% or more in the tissue-normalized AUC values in normal brain gray matter tissue (wCV = 0.40) suggests that an increase has occurred with 95% confidence, whereas a decrease of 80% or more with respect to baseline suggests that a decrease has occurred with 95% confidence. This article provides the rationale for these claims and the compliance activities needed to achieve these claims. Potential updates to incorporate new data based on advances in technology and clinical care in the Profile are also discussed.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA244100,PS-ON,"Tumor-Immune, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.jcyt.2024.08.002,Cytotherapy,39243253,https://pubmed.ncbi.nlm.nih.gov/39243253,Expansion of tumor-infiltrating and marrow-infiltrating lymphocytes from pediatric malignant solid tumors,2025,"Immunotherapy, Pediatrics, Solid Tumors, Cellular Therapy, Tumor-infiltrating Lymphocytes","Jonathan Metts, Madeline Rodriguez-Valentin, Jonathan Hensel, Alex Alfaro, Christopher W Snyder, Odion Binitie, Caroline Chebli, Hector Monforte, Shari Pilon-Thomas, John Mullinax","Introduction: The expansion of tumor-infiltrating lymphocytes (TIL) for adoptive cellular therapy is under investigation in many solid tumors of adulthood. Marrow-infiltrating lymphocytes (MIL) have demonstrated antitumor reactivity preclinically. Successful expansion of TIL/MIL has not been reported across pediatric solid tumor histologies. The objective of this study was to demonstrate successful expansion of TIL from pediatric solid tumors for translation in an adoptive cell therapy (ACT) treatment strategy. Methods: A prospective study of TIL/MIL expansion was performed on solid tumors of pediatric patients undergoing standard-of-care procedures. TIL/MIL expansions were performed in the presence of high-dose interleukin 2. To demonstrate a full-scale expansion to clinically-relevant cell doses for TIL therapy, initial TIL culture was followed by a rapid expansion protocol for select patients. Expanded specimens were analyzed for phenotype by flow cytometry and for anti-tumor reactivity by the interferon-gamma release assay. Results: Eighteen tumor samples were obtained. Initial TIL cultures were successfully generated from 14/18 samples (77.7%). A median of 5.52 × 107 (range: 2.5 × 106-3.23 × 108) cells were produced from initial cultures, with 46.9% expressing a CD3 phenotype (46.9%). Eight samples underwent rapid expansion, demonstrating a median 458-fold expansion and a CD3 phenotype of 98%. Initial MIL cultures were successfully generated from five samples, with a predominantly CD3 phenotype (45.2%). Sufficient tumor tissue was only available for seven TIL samples to be tested for reactivity; none demonstrated responsiveness to autologous tumor. Conclusions: TIL and MIL expansion from pediatric solid tumors was successful, including the full-scale expansion process. This data supports translation to an ACT-TIL treatment strategy in the pediatric population and thus a Phase I trial of ACT-TIL in pediatric high-risk solid tumors is planned.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access \ No newline at end of file diff --git a/annotations/input/nov_datasets.csv b/annotations/input/nov_datasets.csv deleted file mode 100644 index cd53ba0b..00000000 --- a/annotations/input/nov_datasets.csv +++ /dev/null @@ -1,18 +0,0 @@ -Component,DatasetView_id,Dataset Pubmed Id,Dataset Grant Number,Dataset Name,Dataset Alias,Dataset Description,Dataset Design,Dataset Assay,Dataset Species,Dataset Tumor Type,Dataset Tissue,Dataset Url,Dataset File Formats,Id,entityId -DatasetView,,39333113,CA217297,3D chromatin architecture of drug-tolerant cancer cells at single-cell resolution [scHi-C],GSE194308,"Anticancer drug therapy generally elicits the drug tolerance after long-term treatment. Recent studies suggested that 3D chromatin structures of cancer cells were intimately linked to drug resistance. However, 3D chromatin structures in drug-tolerant cancer cells at single-cell resolution haven’t been elucidated. Here we performed single-cell Hi-C (scHi-C) analysis to examine the 3D chromatin structures in three stages of breast cancer cells.","To fully understand the 3D chromatin structures of drug-tolerant cancer cells at single-cell resolution, we designed scHi-C approach for analyzing a breast cancer cell model system, MCF7, MCF7M1 and MCF7TR cells. A total of 293 cells (89 MCF7 cells, 91 MCF7M1 cells, 113 MCF7TR cells) were used for scHi-C profiling.","Computational Modeling, Single Cell RNA-Sequencing",Human,Breast Carcinoma,Breast,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE194308,,, -DatasetView,,39333113,CA217297,3D chromatin architecture of drug-tolerant cancer cells at single-cell resolution (scRNA-seq dataset),GSE195610,"Anticancer drug therapy generally elicits the drug tolerance after long-term treatment. Recent studies suggested that 3D chromatin structures of cancer cells were intimately linked to drug resistance. However, 3D chromatin structures in drug-tolerant cancer cells at single-cell resolution haven’t been elucidated. Here we performed single-cell Hi-C (scHi-C) analysis to examine the 3D chromatin structures in three stages of breast cancer cells. Then Single-cell RNA-seq data were integrated with scHi-C data.","To fully understand the 3D chromatin structures of drug-tolerant cancer cells at single-cell resolution, we designed scHi-C approach for analyzing a breast cancer cell model system, MCF7, MCF7M1 and MCF7TR cells. A total of 293 cells (89 MCF7 cells, 91 MCF7M1 cells, 113 MCF7TR cells) were used for scHi-C profiling and 22,425 cells (6,172 MCF7 cells, 10,156 MCF7M1 cells, 6,097 MCF7TR cells) were used for single-cell RNA-seq (scRNA-seq) profiling . This is the dataset stored for scRNA-seq data.","Computational Modeling, Single Cell RNA-Sequencing",Human,Breast Carcinoma,Breast,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE195610,,, -DatasetView,,39333113,CA217297,3D chromatin architecture of drug-tolerant cancer cells at single-cell resolution,GSE195611,This SuperSeries is composed of the SubSeries listed below.,Refer to individual Series,"Computational Modeling, Single Cell RNA-Sequencing",Human,Breast Carcinoma,Breast,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE195611,,, -DatasetView,,39333113,CA217297,3D chromatin architecture of drug-tolerant cancer cells at single-cell resolution (Reference dataset of population cells.,GSE195810,"Anticancer drug therapy generally elicits the drug tolerance after long-term treatment. Recent studies suggested that 3D chromatin structures of cancer cells were intimately linked to drug resistance. However, 3D chromatin structures in drug-tolerant cancer cells at single-cell resolution haven’t been elucidated. Here we performed single-cell Hi-C (scHi-C) analysis to examine the 3D chromatin structures in three stages of breast cancer cells. Population cells Hi-C data as the reference.","To fully understand the 3D chromatin structures of drug-tolerant cancer cells at single-cell resolution, we designed scHi-C approach for analyzing a breast cancer cell model system, MCF7, MCF7M1 and MCF7TR cells. A total of 293 cells (89 MCF7 cells, 91 MCF7M1 cells, 113 MCF7TR cells) were used for scHi-C profiling. Population cells Hi-C data as the reference. This is the dataset stored for population cells.","Computational Modeling, Single Cell RNA-Sequencing",Human,Breast Carcinoma,Breast,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE195810,,, -DatasetView,,39333113,CA217297,3D chromatin architecture of drug-tolerant cancer cells at single-cell resolution (scDNA-seq dataset),GSE239435,"Anticancer drug therapy generally elicits the drug tolerance after long-term treatment. Recent studies suggested that 3D chromatin structures of cancer cells were intimately linked to drug resistance. However, 3D chromatin structures in drug-tolerant cancer cells at single-cell resolution haven’t been elucidated. Here we performed single-cell Hi-C (scHi-C) analysis to examine the 3D chromatin structures in three stages of breast cancer cells. Then Single-cell RNA-seq data were integrated with scHi-C data. scDNA-seq data were also been generated.","To fully understand the 3D chromatin structures of drug-tolerant cancer cells at single-cell resolution, we designed scHi-C approach for analyzing a breast cancer cell model system, MCF7, MCF7M1 and MCF7TR cells. A total of 293 cells (89 MCF7 cells, 91 MCF7M1 cells, 113 MCF7TR cells) were used for scHi-C profiling and 22,425 cells (6,172 MCF7 cells, 10,156 MCF7M1 cells, 6,097 MCF7TR cells) were used for single-cell RNA-seq (scRNA-seq) profiling . Total of 105 cells (33 of MCF7 cells, 33 of MCF7M1 and 39 of MCFTR cells) were used for single-cell DNA-seq (scDNA-seq) profiling This is the dataset stored for scDNA-seq data.","Computational Modeling, Single Cell RNA-Sequencing",Human,Breast Carcinoma,Breast,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE239435,,, -DatasetView,,38823395,CA225088,A myeloid maturation program initiated by nucleotide depletion during S phase [CRISPRi screen],GSE211065,"Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.","Genome-wide and sublibrary CRISPRi screens were performed in ER-Hoxa9, THP-1, and K562 cells with and without BRQ treatment.",Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE211065,,, -DatasetView,,38823395,CA225089,Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress,GSE172335,This SuperSeries is composed of the SubSeries listed below.,Refer to individual Series,Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE172335,,, -DatasetView,,38823395,CA225090,A myeloid maturation program initiated by nucleotide depletion during S phase [Cut & Run],GSE172296,"Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.","Cell lines were treated with vehicle or drug for the indicated time, and CUT&RUN was performed with the indicated antibodies.",Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE172296,,, -DatasetView,,38823395,CA225091,A myeloid maturation program initiated by nucleotide depletion during S phase [ATAC-Seq],GSE172299,"Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.",Cell lines were treated with vehicle or drug for the indicated times and ATACseq was performed.,Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE172299,,, -DatasetView,,38823395,CA225092,A myeloid maturation program initiated by nucleotide depletion during S phase [ery_scrnaseq],GSE262392,"Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.","scRNAseq was performed on erythroid progenitors differentiated from human CD34+ HSPCs at day 11 and 14; they were treated with DMSO, HU, or APH starting at day 7.",Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE262392,,, -DatasetView,,38823395,CA225093,A myeloid maturation program initiated by nucleotide depletion during S phase [scRNA-seq],GSE172300,"Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.","Cell lines were treated with vehicle or drug for the indicated times and barcoded with MULTI-seq, and single-cell transcriptomes were sequenced on the 10X Genomics platform.",Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE172300,,, -DatasetView,,38823395,CA225094,A myeloid maturation program initiated by nucleotide depletion during S phase [RNA-Seq],GSE172333,"Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.","Cell lines were treated with vehicle or drug for the indicated times, RNA was extracted, and RNA sequencing was performed.",Computational Modeling,Multispecies,Acute Myeloid Leukemia ,Blood,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE172333,,, -DatasetView,,39058094,CA224013,MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer [RNA-seq],GSE242516,The effect of gene perturbation on the transcriptome was evaluated in human Cas9 expressing cancer cell lines,"Human pancreatic cancer cell lines were cultured in DMEM,RPMI or HITES supplemented with 5 or 10% fetal bovine serum (FBS). RNA-extraction (Triazol) and Poly-A followed by library preparation was performed in accordance to manufacturer’s instructions (Illumina Truseq Kit).","Western Blotting, Immunohistochemistry Staining Method, Fluorescence Microscopy, RT-qPCR, Immunoprecipitation",Human,Pan-Cancer,Not Applicable,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242516,,, -DatasetView,,39058094,CA224014,MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer,GSE242517,This SuperSeries is composed of the SubSeries listed below.,Refer to individual Series,"Western Blotting, Immunohistochemistry Staining Method, Fluorescence Microscopy, RT-qPCR, Immunoprecipitation",Human,Pan-Cancer,Not Applicable,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242517,,, -DatasetView,,39058094,CA224015,MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer [CUT&RUN],GSE241897,The effect of gene perturbation on the histone mark H3K27ac was evaluated in human Cas9 expressing MDA-MB231 cancers,Human pancreatic cancer cell lines were cultured in DMEM supplemented with 10% fetal bovine serum (FBS). CUT&RUN was performed according to manufacturer’s instructions (EpiCypher-CUTANA Kit) and Sequencing libraries were generated using Ultra II DNA Library Prep Kit (NEBNext),"Western Blotting, Immunohistochemistry Staining Method, Fluorescence Microscopy, RT-qPCR, Immunoprecipitation",Human,Pan-Cancer,Not Applicable,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE241897,,, -DatasetView,,39394434,"CA274492, CA209975",Bulk RNA-sequencing of mouse prostate tumors initiated by transplantation of engineered organoids.,GSE246251,Purpose: Profile global expression of prostatic tumors to compare with published datasets. Methods: Prostate tumors were flash frozen followed by processed for total RNA using the RNeasy kit (Qiagen). Samples were submitted for polyA library preparation and bulk RNA-sequencing. Conclusions: Global gene expression profiling and comparison of prostate tumor genotypes suggests differential enrichment of neuroendocrine signatures that match established human neuroendocrine prostate cancer expression signatures.,"To investigate the molecular landscape of transplanted PtPM and RPM orthotopic prostate tumors, n = 10 PtPM and n = 8 RPM tumors isolated at early or late time points were subjected bulk RNA-sequencing.","Murine Model, Immunohistochemistry Staining Method, RNA Sequencing",Mouse,Prostate Adenocarcinoma,Prostate Gland,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE246251,,, -DatasetView,,39330965,CA228963,HCC spatial transcriptomic profiling reveals significant and potentially targetable cancer-endothelial interactions,GSE277104,"HCC is a highly vascular tumor, and many effective drug regimens target the tumor blood vessels. Prior bulk HCC subtyping data used bulk transcriptomes, which contained a mixture of parenchymal and stromal contributions. Using cell type–specific spatial transcriptomics techniques to separate cancer cells and endothelial cells applied to a set of 41 resected HCC tissue specimens, we report that the prior Hoshida bulk transcriptional subtyping schema is driven largely by an endothelial fraction, show an alternative tumor-specific schema has potential prognostic value, and use spatially paired ligand-receptor analyses to identify known and novel (LGALS9 tumor-HAVCR2 vessel) signaling relationships that drive HCC biology in a subtype-specific and potentially targetable manner. Our study leverages spatial gene expression profiling technologies to dissect HCC heterogeneity and identify heterogeneous sig- naling relationships between cancer cells and their endothelial cells. Future validation and expansion of these findings may validate novel cancer- endothelial cell interactions and related drug targets.",We used cell type–specific spatial transcriptomics techniques (Nanostring GeoMx) to separate cancer cells and endothelial cells applied to a set of 41 resected HCC tissue specimens.,Computational Modeling,,Hepatocellular Carcinoma,Liver,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE277104,,, \ No newline at end of file diff --git a/annotations/input/nov_filepaths.csv b/annotations/input/nov_filepaths.csv deleted file mode 100644 index 61acd824..00000000 --- a/annotations/input/nov_filepaths.csv +++ /dev/null @@ -1,45 +0,0 @@ -File Paths,folderIdPublication -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA274499_publication.csv,syn43447156 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA267170_publication.csv,syn43447074 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA217297_publication.csv,syn32698273 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA224013_publication.csv,syn35270551 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA274502_publication.csv,syn43447174 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA209975_publication.csv,syn32698159 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA217376_publication.csv,syn32698091 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA217378_publication.csv,syn32698086 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA253540_publication.csv,syn32698462 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA224012_publication.csv,syn35270567 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA214354_publication.csv,syn32698033 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-/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA209891_publication.csv,syn32698008 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA283114_publication.csv,syn53212977 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA238720_publication.csv,syn32698104 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA232216_publication.csv,syn32698110 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA268069_publication.csv,syn35270515 -/Users/anath/Documents/code/mc2-center-dcc/annotations/output/output_nov/CA210181_publication.csv,syn32698212 diff --git a/annotations/input/nov_pubs.csv b/annotations/input/nov_pubs.csv deleted file mode 100644 index 05b18fc6..00000000 --- a/annotations/input/nov_pubs.csv +++ /dev/null @@ -1,48 +0,0 @@ -Component,Publication Grant Number,Publication Consortium Name,Publication Theme Name,Publication Doi,Publication Journal,Pubmed Id,Pubmed Url,Publication Title,Publication Year,Publication Keywords,Publication Authors,Publication Abstract,Publication Assay,Publication Tumor Type,Publication Tissue,Publication Dataset Alias,Publication Accessibility -PublicationView,CA210190,PS-ON,"Microenvironment, Metastasis, Tumor-Immune",https://doi.org/10.1002/sim.10256,Stat Med,39422157,https://pubmed.ncbi.nlm.nih.gov/39422157,Phase I/II Design for Selecting Subgroup-Specific Optimal Biological Doses for Prespecified Subgroups,2024,"Immunotherapy, Subgroups, Bayesian Design, Optimal Biological Dose, Spike And Slab","Sydney Porter, Thomas A Murray, Anne Eaton","We propose a phase I/II trial design to support dose-finding when the optimal biological dose (OBD) may differ in two prespecified patient subgroups. The proposed design uses a utility function to quantify efficacy-toxicity trade-offs, and a Bayesian model with spike and slab prior distributions for the subgroup effect on toxicity and efficacy to guide dosing and to facilitate identifying either subgroup-specific OBDs or a common OBD depending on the resulting trial data. In a simulation study, we find the proposed design performs nearly as well as a design that ignores subgroups when the dose-toxicity and dose-efficacy relationships are the same in both subgroups, and nearly as well as a design with independent dose-finding within each subgroup when these relationships differ across subgroups. In other words, the proposed adaptive design performs similarly to the design that would be chosen if investigators possessed foreknowledge about whether the dose-toxicity and/or dose-efficacy relationship differs across two prespecified subgroups. Thus, the proposed design may be effective for OBD selection when uncertainty exists about whether the OBD differs in two prespecified subgroups.",,,,,Open Access -PublicationView,CA250040,PS-ON,Tumor-Immune,https://doi.org/10.1038/s41467-024-52565-2,Nat Commun,39333505,https://pubmed.ncbi.nlm.nih.gov/39333505,Mechanical force regulates ligand binding and function of PD-1,2024,,"Kaitao Li, Paul Cardenas-Lizana, Jintian Lyu, Anna V Kellner, Menglan Li, Peiwen Cong, Valencia E Watson, Zhou Yuan, Eunseon Ahn, Larissa Doudy, Zhenhai Li, Khalid Salaita, Rafi Ahmed, Cheng Zhu","Despite the success of PD-1 blockade in cancer therapy, how PD-1 initiates signaling remains unclear. Soluble PD-L1 is found in patient sera and can bind PD-1 but fails to suppress T cell function. Here, we show that PD-1 function is reduced when mechanical support on ligand is removed. Mechanistically, cells exert forces to PD-1 and prolong bond lifetime at forces <7 pN (catch bond) while accelerate dissociation at forces >8pN (slip bond). Molecular dynamics of PD-1-PD-L2 complex suggests force may cause relative rotation and translation between the two molecules yielding distinct atomic contacts not observed in the crystal structure. Compared to wild-type, PD-1 mutants targeting the force-induced distinct interactions maintain the same binding affinity but suppressed/eliminated catch bond, lowered rupture force, and reduced inhibitory function. Our results uncover a mechanism for cells to probe the mechanical support of PD-1-PD-Ligand bonds using endogenous forces to regulate PD-1 signaling.",,,,,Open Access -PublicationView,,,,https://doi.org/10.1182/bloodadvances.2023012529,Blood Adv,38324726,https://pubmed.ncbi.nlm.nih.gov/38324726,Cysteine-binding adjuvant enhances survival and promotes immune function in a murine model of acute myeloid leukemia,2024,,"Anna J Slezak, Kevin Chang, Taryn N Beckman, Kirsten C Refvik, Aaron T Alpar, Abigail L Lauterbach, Ani Solanki, Jung Woo Kwon, Suzana Gomes, Aslan Mansurov, Jeffrey A Hubbell","Abstract: Therapeutic vaccination has long been a promising avenue for cancer immunotherapy but is often limited by tumor heterogeneity. The genetic and molecular diversity between patients often results in variation in the antigens present on cancer cell surfaces. As a result, recent research has focused on personalized cancer vaccines. Although promising, this strategy suffers from time-consuming production, high cost, inaccessibility, and targeting of a limited number of tumor antigens. Instead, we explore an antigen-agnostic polymeric in situ cancer vaccination platform for treating blood malignancies, in our model here with acute myeloid leukemia (AML). Rather than immunizing against specific antigens or targeting adjuvant to specific cell-surface markers, this platform leverages a characteristic metabolic and enzymatic dysregulation in cancer cells that produces an excess of free cysteine thiols on their surfaces. These thiols increase in abundance after treatment with cytotoxic agents such as cytarabine, the current standard of care in AML. The resulting free thiols can undergo efficient disulfide exchange with pyridyl disulfide (PDS) moieties on our construct and allow for in situ covalent attachment to cancer cell surfaces and debris. PDS-functionalized monomers are incorporated into a statistical copolymer with pendant mannose groups and TLR7 agonists to target covalently linked antigen and adjuvant to antigen-presenting cells in the liver and spleen after IV administration. There, the compound initiates an anticancer immune response, including T-cell activation and antibody generation, ultimately prolonging survival in cancer-bearing mice.",,,,,Open Access -PublicationView,CA217297,CSBC,"Epigenetics, Drug Resistance/Sensitivity",https://doi.org/10.1038/s41467-024-52440-0,Nat Commun,39333113,https://pubmed.ncbi.nlm.nih.gov/39333113,Integration of scHi-C and scRNA-seq data defines distinct 3D-regulated and biological-context dependent cell subpopulations,2024,,"Yufan Zhou, Tian Li, Lavanya Choppavarapu, Kun Fang, Shili Lin, Victor X Jin","An integration of 3D chromatin structure and gene expression at single-cell resolution has yet been demonstrated. Here, we develop a computational method, a multiomic data integration (MUDI) algorithm, which integrates scHi-C and scRNA-seq data to precisely define the 3D-regulated and biological-context dependent cell subpopulations or topologically integrated subpopulations (TISPs). We demonstrate its algorithmic utility on the publicly available and newly generated scHi-C and scRNA-seq data. We then test and apply MUDI in a breast cancer cell model system to demonstrate its biological-context dependent utility. We find the newly defined topologically conserved associating domain (CAD) is the characteristic single-cell 3D chromatin structure and better characterizes chromatin domains in single-cell resolution. We further identify 20 TISPs uniquely characterizing 3D-regulated breast cancer cellular states. We reveal two of TISPs are remarkably resemble to high cycling breast cancer persister cells and chromatin modifying enzymes might be functional regulators to drive the alteration of the 3D chromatin structures. Our comprehensive integration of scHi-C and scRNA-seq data in cancer cells at single-cell resolution provides mechanistic insights into 3D-regulated heterogeneity of developing drug-tolerant cancer cells.",,,,"GSE194308, GSE195610, GSE195611, GSE195810, GSE239435",Open Access -PublicationView,CA274499,CSBC,"Oncogenic Stress, Metabolism",https://doi.org/10.1016/j.jbc.2024.105669,J Biol Chem,38272221,https://pubmed.ncbi.nlm.nih.gov/38272221,Chromosomal passenger complex condensates generate parallel microtubule bundles in vitro,2024,"Chromosomal Instability, Aurora Kinase, Mitotic Spindle, Chromosomal Passenger Complex, Mtoc, Midzone, Inner Centromere","Ewa Niedzialkowska, Tan M Truong, Luke A Eldredge, Aamir Ali, Stefanie Redemann, P Todd Stukenberg","The mitotic spindle contains many bundles of microtubules (MTs) including midzones and kinetochore fibers, but little is known about how bundled structures are formed. Here, we show that the chromosomal passenger complex (CPC) purified from Escherichia coli undergoes liquid-liquid demixing in vitro. An emergent property of the resultant condensates is to generate parallel MT bundles when incubated with free tubulin and GTP in vitro. We demonstrate that MT bundles emerge from CPC droplets with protruding minus ends that then grow into long and tapered MT structures. During this growth, we found that the CPC in these condensates apparently reorganize to coat and bundle the resulting MT structures. CPC mutants attenuated for liquid-liquid demixing or MT binding prevented the generation of parallel MT bundles in vitro and reduced the number of MTs present at spindle midzones in HeLa cells. Our data demonstrate that an in vitro biochemical activity to produce MT bundles emerges after the concentration of the CPC and provides models for how cells generate parallel-bundled MT structures that are important for the assembly of the mitotic spindle. Moreover, these data suggest that cells contain MT-organizing centers that generate MT bundles that emerge with the opposite polarity from centrosomes.",,,,,Open Access -PublicationView,CA253540,CSBC,"Heterogeneity, Drug Resistance/Sensitivity",https://doi.org/10.1038/s41540-024-00345-5,NPJ Syst Biol Appl,38365857,https://pubmed.ncbi.nlm.nih.gov/38365857,Forum on immune digital twins: a meeting report,2024,,"Reinhard Laubenbacher, Fred Adler, Gary An, Filippo Castiglione, Stephen Eubank, Luis L Fonseca, James Glazier, Tomas Helikar, Marti Jett-Tilton, Denise Kirschner, Paul Macklin, Borna Mehrad, Beth Moore, Virginia Pasour, Ilya Shmulevich, Amber Smith, Isabel Voigt, Thomas E Yankeelov, Tjalf Ziemssen","Medical digital twins are computational models of human biology relevant to a given medical condition, which are tailored to an individual patient, thereby predicting the course of disease and individualized treatments, an important goal of personalized medicine. The immune system, which has a central role in many diseases, is highly heterogeneous between individuals, and thus poses a major challenge for this technology. In February 2023, an international group of experts convened for two days to discuss these challenges related to immune digital twins. The group consisted of clinicians, immunologists, biologists, and mathematical modelers, representative of the interdisciplinary nature of medical digital twin development. A video recording of the entire event is available. This paper presents a synopsis of the discussions, brief descriptions of ongoing digital twin projects at different stages of progress. It also proposes a 5-year action plan for further developing this technology. The main recommendations are to identify and pursue a small number of promising use cases, to develop stimulation-specific assays of immune function in a clinical setting, and to develop a database of existing computational immune models, as well as advanced modeling technology and infrastructure.",,,,,Open Access -PublicationView,CA228608,PDMC,"Metastasis, Method/Assay Development",https://doi.org/10.1126/sciadv.adk8801,Sci Adv,39485847,https://pubmed.ncbi.nlm.nih.gov/39485847,Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis,2024,,"Spencer D Shelton, Sara House, Luiza Martins Nascentes Melo, Vijayashree Ramesh, Zhenkang Chen, Tao Wei, Xun Wang, Claire B Llamas, Siva Sai Krishna Venigalla, Cameron J Menezes, Gabriele Allies, Jonathan Krystkiewicz, Jonas Rösler, Sven W Meckelmann, Peihua Zhao, Florian Rambow, Dirk Schadendorf, Zhiyu Zhao, Jennifer G Gill, Ralph J DeBerardinis, Sean J Morrison, Alpaslan Tasdogan, Prashant Mishra","Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood.",,,,,Open Access -PublicationView,CA214411,TEC,"Heterogeneity, Microenvironment, Drug Resistance/Sensitivity",https://doi.org/10.1002/advs.202001447,Adv Sci (Weinh),33042756,https://pubmed.ncbi.nlm.nih.gov/33042756,Screening Cancer Immunotherapy: When Engineering Approaches Meet Artificial Intelligence,2020,"Artificial intelligence, Drug screening, Tissue engineering, Cancer Immunotherapy, High‐throughput Screening","Xingwu Zhou, Moyuan Qu, Peyton Tebon, Xing Jiang, Canran Wang, Yumeng Xue, Jixiang Zhu, Shiming Zhang, Rahmi Oklu, Shiladitya Sengupta, Wujin Sun, Ali Khademhosseini","Immunotherapy is a class of promising anticancer treatments that has recently gained attention due to surging numbers of FDA approvals and extensive preclinical studies demonstrating efficacy. Nevertheless, further clinical implementation has been limited by high variability in patient response to different immunotherapeutic agents. These treatments currently do not have reliable predictors of efficacy and may lead to side effects. The future development of additional immunotherapy options and the prediction of patient-specific response to treatment require advanced screening platforms associated with accurate and rapid data interpretation. Advanced engineering approaches ranging from sequencing and gene editing, to tumor organoids engineering, bioprinted tissues, and organs-on-a-chip systems facilitate the screening of cancer immunotherapies by recreating the intrinsic and extrinsic features of a tumor and its microenvironment. High-throughput platform development and progress in artificial intelligence can also improve the efficiency and accuracy of screening methods. Here, these engineering approaches in screening cancer immunotherapies are highlighted, and a discussion of the future perspectives and challenges associated with these emerging fields to further advance the clinical use of state-of-the-art cancer immunotherapies are provided.",,,,,Open Access -PublicationView,CA225088,CSBC,"Microenvironment, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.devcel.2024.05.010,Dev Cell,38823395,https://pubmed.ncbi.nlm.nih.gov/38823395,Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress,2024,"Metabolism, Differentiation, Nucleotides, Cancer, Replication, Hematopoiesis, Epigenetics, Cell Fate, Replication Stress, Dependencies, Cell State","Brian T Do, Peggy P Hsu, Sidney Y Vermeulen, Zhishan Wang, Taghreed Hirz, Keene L Abbott, Najihah Aziz, Joseph M Replogle, Stefan Bjelosevic, Jonathan Paolino, Samantha A Nelson, Samuel Block, Alicia M Darnell, Raphael Ferreira, Hanyu Zhang, Jelena Milosevic, Daniel R Schmidt, Christopher Chidley, Isaac S Harris, Jonathan S Weissman, Yana Pikman, Kimberly Stegmaier, Sihem Cheloufi, Xiaofeng A Su, David B Sykes, Matthew G Vander Heiden","Control of cellular identity requires coordination of developmental programs with environmental factors such as nutrient availability, suggesting that perturbing metabolism can alter cell state. Here, we find that nucleotide depletion and DNA replication stress drive differentiation in human and murine normal and transformed hematopoietic systems, including patient-derived acute myeloid leukemia (AML) xenografts. These cell state transitions begin during S phase and are independent of ATR/ATM checkpoint signaling, double-stranded DNA break formation, and changes in cell cycle length. In systems where differentiation is blocked by oncogenic transcription factor expression, replication stress activates primed regulatory loci and induces lineage-appropriate maturation genes despite the persistence of progenitor programs. Altering the baseline cell state by manipulating transcription factor expression causes replication stress to induce genes specific for alternative lineages. The ability of replication stress to selectively activate primed maturation programs across different contexts suggests a general mechanism by which changes in metabolism can promote lineage-appropriate cell state transitions.",,,,"GSE211065, GSE172335, GSE172296, GSE172299, GSE262392, GSE172300, GSE172333",Open Access -PublicationView,CA253547,CSBC,Tumor-Immune,https://doi.org/10.1158/2159-8290.cd-24-0604,Cancer Discov,39363746,https://pubmed.ncbi.nlm.nih.gov/39363746,Transforming Cancer Research through Informatics,2024,,"Juli D Klemm, Dinah S Singer, Jill P Mesirov","For more than three decades, concurrent advances in laboratory technologies and computer science have driven the rise of cancer informatics. Today, software tools for cancer research are indispensable to the entire cancer research enterprise.",,,,,Open Access -PublicationView,CA268069,CCBIR,"Immunotherapy, Microenvironment, Platform Development, Tumor-Immune",https://doi.org/10.3390/metabo14100550,Metabolites,39452931,https://pubmed.ncbi.nlm.nih.gov/39452931,Multi-Modal Investigation of Metabolism in Murine Breast Cancer Cell Lines Using Fluorescence Lifetime Microscopy and Hyperpolarized 13C-Pyruvate Magnetic Resonance Spectroscopy,2024,"Metabolism, Breast cancer, Metastatic potential, Flim, Mrs, Hyperpolarized, Carbon-13","Sarah Erickson-Bhatt, Benjamin L Cox, Erin Macdonald, Jenu V Chacko, Paul Begovatz, Patricia J Keely, Suzanne M Ponik, Kevin W Eliceiri, Sean B Fain","Background/Objectives: Despite the role of metabolism in breast cancer metastasis, we still cannot predict which breast tumors will progress to distal metastatic lesions or remain dormant. This work uses metabolic imaging to study breast cancer cell lines (4T1, 4T07, and 67NR) with differing metastatic potential in a 3D collagen gel bioreactor system. Methods: Within the bioreactor, hyperpolarized magnetic resonance spectroscopy (HP-MRS) is used to image lactate/pyruvate ratios, while fluorescence lifetime imaging microscopy (FLIM) of endogenous metabolites measures metabolism at the cellular scale. Results: HP-MRS results showed no lactate peak for 67NR and a comparatively large lactate/pyruvate ratio for both 4T1 and 4T07 cell lines, suggestive of greater pyruvate utilization with greater metastatic potential. Similar patterns were observed using FLIM with significant increases in FAD intensity, redox ratio, and NAD(P)H lifetime. The lactate/pyruvate ratio was strongly correlated to NAD(P)H lifetime, consistent with the role of NADH as an electron donor for the glycolytic pathway, suggestive of an overall upregulation of metabolism (both glycolytic and oxidative), for the 4T07 and 4T1 cell lines compared to the non-metastatic 67NR cell line. Conclusions: These findings support a complementary role for HP-MRS and FLIM enabled by a novel collagen gel bioreactor system to investigate metastatic potential and cancer metabolism.",,,,,Open Access -PublicationView,CA253540,CSBC,"Heterogeneity, Drug Resistance/Sensitivity",https://doi.org/10.1038/s41540-024-00441-6,NPJ Syst Biol Appl,39420005,https://pubmed.ncbi.nlm.nih.gov/39420005,Computational identification of surface markers for isolating distinct subpopulations from heterogeneous cancer cell populations,2024,,"Andrea L Gardner, Tyler A Jost, Daylin Morgan, Amy Brock","Intratumor heterogeneity reduces treatment efficacy and complicates our understanding of tumor progression and there is a pressing need to understand the functions of heterogeneous tumor cell subpopulations within a tumor, yet systems to study these processes in vitro are limited. Single-cell RNA sequencing (scRNA-seq) has revealed that some cancer cell lines include distinct subpopulations. Here, we present clusterCleaver, a computational package that uses metrics of statistical distance to identify candidate surface markers maximally unique to transcriptomic subpopulations in scRNA-seq which may be used for FACS isolation. With clusterCleaver, ESAM and BST2/tetherin were experimentally validated as surface markers which identify and separate major transcriptomic subpopulations within MDA-MB-231 and MDA-MB-436 cells, respectively. clusterCleaver is a computationally efficient and experimentally validated workflow for identification of surface markers for tracking and isolating transcriptomically distinct subpopulations within cell lines. This tool paves the way for studies on coexisting cancer cell subpopulations in well-defined in vitro systems.",,,,,Open Access -PublicationView,CA225566,PS-ON,Microenvironment,https://doi.org/10.1039/d4sm00683f,Soft Matter,39105242,https://pubmed.ncbi.nlm.nih.gov/39105242,Rethinking nuclear shaping: insights from the nuclear drop model,2024,,"Richard B Dickinson, Samere Abolghasemzade, Tanmay P Lele","Changes in the nuclear shape caused by cellular shape changes are generally assumed to reflect an elastic deformation from a spherical nuclear shape. Recent evidence, however, suggests that the nuclear lamina, which forms the outer nuclear surface together with the nuclear envelope, possesses more area than that of a sphere of the same volume. This excess area manifests as folds/wrinkles in the nuclear surface in rounded cells and allows facile nuclear flattening during cell spreading without any changes in nuclear volume or surface area. When the lamina becomes smooth and taut, it is inextensible, and supports a surface tension. At this point, it is possible to mathematically calculate the limiting nuclear shape purely based on geometric considerations. In this paper, we provide a commentary on the ""nuclear drop model"" which seeks to integrate the above features. We outline its testable physical properties and explore its biological implications.",,,,,Open Access -PublicationView,CA282451,TEC,"Microenvironment, Experimental Model Development",https://doi.org/10.1002/adhm.202402571,Adv Healthc Mater,39498750,https://pubmed.ncbi.nlm.nih.gov/39498750,3D-Printed Polymeric Biomaterials for Health Applications. ,2024,,"Yuxiang Zhu, Shenghan Guo, Dharneedar Ravichandran, Arunachalam Ramanathan, M Taylor Sobczak, Alaina F Sacco, Dhanush Patil, Sri Vaishnavi Thummalapalli, Tiffany V Pulido, Jessica N Lancaster, Johnny Yi, Jeffrey L Cornella, David G Lott, Xiangfan Chen, Xuan Mei, Yu Shrike Zhang, Linbing Wang, Xianqiao Wang, Yiping Zhao, Mohammad K Hassan, Lindsay B Chambers, Taylor G Theobald, Sui Yang, Liang Liang, Kenan Song","3D printing, also known as additive manufacturing, holds immense potential for rapid prototyping and customized production of functional health-related devices. With advancements in polymer chemistry and biomedical engineering, polymeric biomaterials have become integral to 3D-printed biomedical applications. However, there still exists a bottleneck in the compatibility of polymeric biomaterials with different 3D printing methods, as well as intrinsic challenges such as limited printing resolution and rates. Therefore, this review aims to introduce the current state-of-the-art in 3D-printed functional polymeric health-related devices. It begins with an overview of the landscape of 3D printing techniques, followed by an examination of commonly used polymeric biomaterials. Subsequently, examples of 3D-printed biomedical devices are provided and classified into categories such as biosensors, bioactuators, soft robotics, energy storage systems, self-powered devices, and data science in bioplotting. The emphasis is on exploring the current capabilities of 3D printing in manufacturing polymeric biomaterials into desired geometries that facilitate device functionality and studying the reasons for material choice. Finally, an outlook with challenges and possible improvements in the near future is presented, projecting the contribution of general 3D printing and polymeric biomaterials in the field of healthcare.",,,,,Open Access -PublicationView,CA245313,TEC,"Microenvironment, Metastasis, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.cell.2024.09.001,Cell,39353436,https://pubmed.ncbi.nlm.nih.gov/39353436,Spatially exploring RNA biology in archival formalin-fixed paraffin-embedded tissues,2024,"Spatiotemporal dynamics, Histopathology, MicroRNA, Whole Transcriptome, Rna Biology, Splicing Isoforms, Spatial Omics, Clinical Ffpe Tissue, Single-nucleotide Rna Variants","Zhiliang Bai, Dingyao Zhang, Yan Gao, Bo Tao, Daiwei Zhang, Shuozhen Bao, Archibald Enninful, Yadong Wang, Haikuo Li, Graham Su, Xiaolong Tian, Ningning Zhang, Yang Xiao, Yang Liu, Mark Gerstein, Mingyao Li, Yi Xing, Jun Lu, Mina L Xu, Rong Fan","The capability to spatially explore RNA biology in formalin-fixed paraffin-embedded (FFPE) tissues holds transformative potential for histopathology research. Here, we present pathology-compatible deterministic barcoding in tissue (Patho-DBiT) by combining in situ polyadenylation and computational innovation for spatial whole transcriptome sequencing, tailored to probe the diverse RNA species in clinically archived FFPE samples. It permits spatial co-profiling of gene expression and RNA processing, unveiling region-specific splicing isoforms, and high-sensitivity transcriptomic mapping of clinical tumor FFPE tissues stored for 5 years. Furthermore, genome-wide single-nucleotide RNA variants can be captured to distinguish malignant subclones from non-malignant cells in human lymphomas. Patho-DBiT also maps microRNA regulatory networks and RNA splicing dynamics, decoding their roles in spatial tumorigenesis. Single-cell level Patho-DBiT dissects the spatiotemporal cellular dynamics driving tumor clonal architecture and progression. Patho-DBiT stands poised as a valuable platform to unravel rich RNA biology in FFPE tissues to aid in clinical pathology evaluation.",,,,,Open Access -PublicationView,CA224013,PDMC,"Heterogeneity, Microenvironment",https://doi.org/10.1158/2159-8290.cd-23-1529,Cancer Discov,39058094,https://pubmed.ncbi.nlm.nih.gov/39058094,MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer,2024,,"Olaf Klingbeil, Damianos Skopelitis, Claudia Tonelli, Toyoki Yoshimoto, Aktan Alpsoy, Maria C Panepinto, Francesca Minicozzi, Joseph R Merrill, Amanda M Cafiero, Disha Aggarwal, Suzanne Russo, Taehoon Ha, Osama E Demerdash, Tse-Luen Wee, David L Spector, Scott K Lyons, David A Tuveson, Paolo Cifani, Christopher R Vakoc","The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.",,,,"GSE242516, GSE242517, GSE241897",Open Access -PublicationView,CA225088,CSBC,"Microenvironment, Drug Resistance/Sensitivity",https://doi.org/10.1038/s41586-024-08031-6,Nature,39385030,https://pubmed.ncbi.nlm.nih.gov/39385030,AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution,2024,,"Amy E Schade, Naiara Perurena, Yoona Yang, Carrie L Rodriguez, Anjana Krishnan, Alycia Gardner, Patrick Loi, Yilin Xu, Van T M Nguyen, G M Mastellone, Natalie F Pilla, Marina Watanabe, Keiichi Ota, Rachel A Davis, Kaia Mattioli, Dongxi Xiang, Jason J Zoeller, Jia-Ren Lin, Stefania Morganti, Ana C Garrido-Castro, Sara M Tolaney, Zhe Li, David A Barbie, Peter K Sorger, Kristian Helin, Sandro Santagata, Simon R V Knott, Karen Cichowski","Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence1. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived1,2. Thus, there is an urgent need to develop more effective treatments. Components of the PI3K pathway represent plausible therapeutic targets; more than 70% of TNBCs have alterations in PIK3CA, AKT1 or PTEN3-6. However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors7. Here we describe a promising AKT-inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once TNBCs are differentiated, these agents kill them by hijacking signals that normally drive mammary gland involution. Using a machine learning approach, we developed a classifier that can be used to predict sensitivity. Together, these findings identify a promising therapeutic strategy for this highly aggressive tumour type and illustrate how deregulated epigenetic enzymes can insulate tumours from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.",,,,,Open Access -PublicationView,CA217378,CSBC,"Heterogeneity, Evolution, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.neuron.2024.07.018,Neuron,39153478,https://pubmed.ncbi.nlm.nih.gov/39153478,Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity,2024,"Rabies virus, Dopamine, Cocaine, Globus pallidus, Ventral tegmental area, Carnosic acid, Drug abuse, voltage-gated potassium channels, Intrinsic Excitability, Chemogenetics, Behavioral Vulnerability","Guilian Tian, Katrina Bartas, May Hui, Lingxuan Chen, Jose J Vasquez, Ghalia Azouz, Pieter Derdeyn, Rían W Manville, Erick L Ho, Amanda S Fang, Yuan Li, Isabella Tyler, Vincent Setola, Jason Aoto, Geoffrey W Abbott, Kevin T Beier","The globus pallidus externus (GPe) is a central component of the basal ganglia circuit that acts as a gatekeeper of cocaine-induced behavioral plasticity. However, the molecular and circuit mechanisms underlying this function are unknown. Here, we show that GPe parvalbumin-positive (GPePV) cells mediate cocaine responses by selectively modulating ventral tegmental area dopamine (VTADA) cells projecting to the dorsomedial striatum (DMS). Interestingly, GPePV cell activity in cocaine-naive mice is correlated with behavioral responses following cocaine, effectively predicting cocaine sensitivity. Expression of the voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability following cocaine was downregulated, contributing to the elevation in GPePV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPePV cell excitability and impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its therapeutic potential to counteract psychostimulant use disorder.",,,,,Open Access -PublicationView,CA209891,CSBC,"Heterogeneity, Evolution, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.molcel.2024.08.010,Mol Cell,39303722,https://pubmed.ncbi.nlm.nih.gov/39303722,Integrated multi-omics analysis of zinc-finger proteins uncovers roles in RNA regulation,2024,"Zinc finger, RNA binding protein, Rna-seq, Multi-omics, Eclip, Cut&run, Znf277, Slam-seq, Znf473, Ribo-stamp","Maya L Gosztyla, Lijun Zhan, Sara Olson, Xintao Wei, Jack Naritomi, Grady Nguyen, Lena Street, Grant A Goda, Francisco F Cavazos, Jonathan C Schmok, Manya Jain, Easin Uddin Syed, Eunjeong Kwon, Wenhao Jin, Eric Kofman, Alexandra T Tankka, Allison Li, Valerie Gonzalez, Eric Lécuyer, Daniel Dominguez, Marko Jovanovic, Brenton R Graveley, Gene W Yeo","RNA interactome studies have revealed that hundreds of zinc-finger proteins (ZFPs) are candidate RNA-binding proteins (RBPs), yet their RNA substrates and functional significance remain largely uncharacterized. Here, we present a systematic multi-omics analysis of the DNA- and RNA-binding targets and regulatory roles of more than 100 ZFPs representing 37 zinc-finger families. We show that multiple ZFPs are previously unknown regulators of RNA splicing, alternative polyadenylation, stability, or translation. The examined ZFPs show widespread sequence-specific RNA binding and preferentially bind proximal to transcription start sites. Additionally, several ZFPs associate with their targets at both the DNA and RNA levels. We highlight ZNF277, a C2H2 ZFP that binds thousands of RNA targets and acts as a multi-functional RBP. We also show that ZNF473 is a DNA/RNA-associated protein that regulates the expression and splicing of cell cycle genes. Our results reveal diverse roles for ZFPs in transcriptional and post-transcriptional gene regulation.",,,,,Open Access -PublicationView,CA217376,CSBC,"Heterogeneity, Epigenetics, Microenvironment, Evolution",https://doi.org/10.1158/2159-8290.cd-24-0573,Cancer Discov,39445720,https://pubmed.ncbi.nlm.nih.gov/39445720,Cancer Prevalence across Vertebrates,2024,,"Zachary T Compton, Walker Mellon, Valerie K Harris, Shawn Rupp, Diego Mallo, Stefania E Kapsetaki, Mallory Wilmot, Ryan Kennington, Kathleen Noble, Cristina Baciu, Lucia N Ramirez, Ashley Peraza, Brian Martins, Sushil Sudhakar, Selin Aksoy, Gabriela Furukawa, Orsolya Vincze, Mathieu Giraudeau, Elizabeth G Duke, Simon Spiro, Edmund Flach, Hannah Davidson, Christopher I Li, Ashley Zehnder, Trevor A Graham, Brigid V Troan, Tara M Harrison, Marc Tollis, Joshua D Schiffman, C Athena Aktipis, Lisa M Abegglen, Carlo C Maley, Amy M Boddy","Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto's paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes.",,,,,Open Access -PublicationView,"CA274492, CA209975",CSBC,"Immunotherapy, Metastasis, Tumor-Immune, Computational Model Development, Microenvironment, Drug Resistance/Sensitivity",https://doi.org/10.1038/s43018-024-00838-6,Nat Cancer,39394434,https://pubmed.ncbi.nlm.nih.gov/39394434,The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1,2024,,"Rodrigo Romero, Tinyi Chu, Tania J González Robles, Perianne Smith, Yubin Xie, Harmanpreet Kaur, Sara Yoder, Huiyong Zhao, Chenyi Mao, Wenfei Kang, Maria V Pulina, Kayla E Lawrence, Anuradha Gopalan, Samir Zaidi, Kwangmin Yoo, Jungmin Choi, Ning Fan, Olivia Gerstner, Wouter R Karthaus, Elisa DeStanchina, Kelly V Ruggles, Peter M K Westcott, Ronan Chaligné, Dana Pe'er, Charles L Sawyers","Lineage plasticity is a hallmark of cancer progression that impacts therapy outcomes, yet the mechanisms mediating this process remain unclear. Here, we introduce a versatile in vivo platform to interrogate neuroendocrine lineage transformation throughout prostate cancer progression. Transplanted mouse prostate organoids with human-relevant driver mutations (Rb1-/-; Trp53-/-; cMyc+ or Pten-/-; Trp53-/-; cMyc+) develop adenocarcinomas, but only those with Rb1 deletion advance to aggressive, ASCL1+ neuroendocrine prostate cancer (NEPC) resistant to androgen receptor signaling inhibitors. Notably, this transition requires an in vivo microenvironment not replicated by conventional organoid culture. Using multiplexed immunofluorescence and spatial transcriptomics, we reveal that ASCL1+ cells arise from KRT8+ luminal cells, progressing into transcriptionally heterogeneous ASCL1+;KRT8- NEPC. Ascl1 loss in established NEPC causes transient regression followed by recurrence, but its deletion before transplantation abrogates lineage plasticity, resulting in castration-sensitive adenocarcinomas. This dynamic model highlights the importance of therapy timing and offers a platform to identify additional lineage plasticity drivers.",,,,GSE246251,Open Access -PublicationView,CA244100,PS-ON,"Drug Resistance/Sensitivity, Tumor-Immune",https://doi.org/10.1038/s41540-024-00439-0,NPJ Syst Biol Appl,39358360,https://pubmed.ncbi.nlm.nih.gov/39358360,Calibrating tumor growth and invasion parameters with spectral spatial analysis of cancer biopsy tissues,2024,,"Stefano Pasetto, Michael Montejo, Mohammad U Zahid, Marilin Rosa, Robert Gatenby, Pirmin Schlicke, Roberto Diaz, Heiko Enderling","The reaction-diffusion equation is widely used in mathematical models of cancer. The calibration of model parameters based on limited clinical data is critical to using reaction-diffusion equation simulations for reliable predictions on a per-patient basis. Here, we focus on cell-level data as routinely available from tissue biopsies used for clinical cancer diagnosis. We analyze the spatial architecture in biopsy tissues stained with multiplex immunofluorescence. We derive a two-point correlation function and the corresponding spatial power spectral distribution. We show that this data-deduced power spectral distribution can fit the power spectrum of the solution of reaction-diffusion equations that can then identify patient-specific tumor growth and invasion rates. This approach allows the measurement of patient-specific critical tumor dynamical properties from routinely available biopsy material at a single snapshot in time.",,,,,Open Access -PublicationView,CA253553,CSBC,"Metabolism, Tumor-Immune",https://doi.org/10.3390/cancers16203525,Cancers (Basel),39456619,https://pubmed.ncbi.nlm.nih.gov/39456619,Beyond Primary HER2 Expression: Trastuzumab Deruxtecan's Efficacy in Brain Metastasis,2024,,"Glori Das, Stephen T C Wong, Hong Zhao","This commentary focuses on the DESTINY-Breast12 study, published in Nature Medicine on 13 September 2024, which evaluates the efficacy of Trastuzumab deruxtecan (T-DXd) in treating HER2-positive advanced breast cancer, including those with brain metastases. We emphasize the broadened clinical potential of T-DXd in treating brain metastases from tumors originally classified as HER2-null or HER2-low, extending beyond its current use for breast cancer. This expanded application of T-DXd could provide new hope to patients dealing with challenging brain metastases, addressing an urgent need for effective treatment options.",,,,,Open Access -PublicationView,CA232137,CSBC,"Heterogeneity, Microenvironment, Metabolism",https://doi.org/10.1093/bib/bbae509,Brief Bioinform,39425527,https://pubmed.ncbi.nlm.nih.gov/39425527,"Building multiscale models with PhysiBoSS, an agent-based modeling tool",2024,"Agent-based Modeling, Boolean Modeling, Multiscale Modeling","Marco Ruscone, Andrea Checcoli, Randy Heiland, Emmanuel Barillot, Paul Macklin, Laurence Calzone, Vincent Noël","Multiscale models provide a unique tool for analyzing complex processes that study events occurring at different scales across space and time. In the context of biological systems, such models can simulate mechanisms happening at the intracellular level such as signaling, and at the extracellular level where cells communicate and coordinate with other cells. These models aim to understand the impact of genetic or environmental deregulation observed in complex diseases, describe the interplay between a pathological tissue and the immune system, and suggest strategies to revert the diseased phenotypes. The construction of these multiscale models remains a very complex task, including the choice of the components to consider, the level of details of the processes to simulate, or the fitting of the parameters to the data. One additional difficulty is the expert knowledge needed to program these models in languages such as C++ or Python, which may discourage the participation of non-experts. Simplifying this process through structured description formalisms-coupled with a graphical interface-is crucial in making modeling more accessible to the broader scientific community, as well as streamlining the process for advanced users. This article introduces three examples of multiscale models which rely on the framework PhysiBoSS, an add-on of PhysiCell that includes intracellular descriptions as continuous time Boolean models to the agent-based approach. The article demonstrates how to construct these models more easily, relying on PhysiCell Studio, the PhysiCell Graphical User Interface. A step-by-step tutorial is provided as Supplementary Material and all models are provided at https://physiboss.github.io/tutorial/.",,,,,Open Access -PublicationView,CA232216,CSBC,"Heterogeneity, Microenvironment, Tumor-Immune",https://doi.org/10.1038/s41540-024-00447-0,NPJ Syst Biol Appl,39389979,https://pubmed.ncbi.nlm.nih.gov/39389979,Systems profiling reveals recurrently dysregulated cytokine signaling responses in ER+ breast cancer patients' blood,2024,,"Brian Orcutt-Jahns, Joao Rodrigues Lima Junior, Emily Lin, Russell C Rockne, Adina Matache, Sergio Branciamore, Ethan Hung, Andrei S Rodin, Peter P Lee, Aaron S Meyer","Cytokines operate in concert to maintain immune homeostasis and coordinate immune responses. In cases of ER+ breast cancer, peripheral immune cells exhibit altered responses to several cytokines, and these alterations are correlated strongly with patient outcomes. To develop a systems-level understanding of this dysregulation, we measured a panel of cytokine responses and receptor abundances in the peripheral blood of healthy controls and ER+ breast cancer patients across immune cell types. Using tensor factorization to model this multidimensional data, we found that breast cancer patients exhibited widespread alterations in response, including drastically reduced response to IL-10 and heightened basal levels of pSmad2/3 and pSTAT4. ER+ patients also featured upregulation of PD-L1, IL6Rα, and IL2Rα, among other receptors. Despite this, alterations in response to cytokines were not explained by changes in receptor abundances. Thus, tensor factorization helped to reveal a coordinated reprogramming of the immune system that was consistent across our cohort.",,,,,Open Access -PublicationView,"CA210181, CA253553","PS-ON, CSBC","Heterogeneity, Microenvironment, Metabolism, Tumor-Immune",https://doi.org/10.1158/2767-9764.crc-24-0235,Cancer Res Commun,39356141,https://pubmed.ncbi.nlm.nih.gov/39356141,Tumor NOS2 and COX2 Spatial Juxtaposition with CD8+ T Cells Promote Metastatic and Cancer Stem Cell Niches that Lead to Poor Outcome in ER- Breast Cancer,2024,,"Lisa A Ridnour, William F Heinz, Robert Y S Cheng, Adelaide L Wink, Noemi Kedei, Milind Pore, Fatima Imtiaz, Elise L Femino, Ana L Gonzalez, Leandro L Coutinho, Rebecca L Moffat, Donna Butcher, Elijah F Edmondson, Xiaoxian Li, Maria Cristina Rangel, Robert J Kinders, Jens Rittscher, Stanley Lipkowitz, Stephen T C Wong, Stephen K Anderson, Daniel W McVicar, Sharon A Glynn, Timothy R Billiar, Jenny C Chang, Stephen M Hewitt, Stefan Ambs, Stephen J Lockett, David A Wink",Significance: This work identifies CD8-NOS2+COX2+ and CD8-NOS2-COX2+ unique cellular neighborhoods that drive the tumor immune spatial architecture of CD8+ T cells predictive of clinical outcome and can be targeted with clinically available NOS inhibitors and NSAIDs.,,,,,Open Access -PublicationView,CA250481,PS-ON,Tumor-Immune,https://doi.org/10.1038/s41746-024-01277-4,NPJ Digit Med,39427044,https://pubmed.ncbi.nlm.nih.gov/39427044,Biologically informed deep neural networks provide quantitative assessment of intratumoral heterogeneity in post treatment glioblastoma,2024,,"Hairong Wang, Michael G Argenziano, Hyunsoo Yoon, Deborah Boyett, Akshay Save, Petros Petridis, William Savage, Pamela Jackson, Andrea Hawkins-Daarud, Nhan Tran, Leland Hu, Kyle W Singleton, Lisa Paulson, Osama Al Dalahmah, Jeffrey N Bruce, Jack Grinband, Kristin R Swanson, Peter Canoll, Jing Li","Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of recurrent glioblastoma. This study addresses the need for non-invasive approaches to map heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We developed BioNet, a biologically-informed neural network, to predict regional distributions of two primary tissue-specific gene modules: proliferating tumor (Pro) and reactive/inflammatory cells (Inf). BioNet significantly outperforms existing methods (p < 2e-26). In cross-validation, BioNet achieved AUCs of 0.80 (Pro) and 0.81 (Inf), with accuracies of 80% and 75%, respectively. In blind tests, BioNet achieved AUCs of 0.80 (Pro) and 0.76 (Inf), with accuracies of 81% and 74%. Competing methods had AUCs lower or around 0.6 and accuracies lower or around 70%. BioNet's voxel-level prediction maps reveal intratumoral heterogeneity, potentially improving biopsy targeting and treatment evaluation. This non-invasive approach facilitates regular monitoring and timely therapeutic adjustments, highlighting the role of ML in precision medicine.",,,,,Open Access -PublicationView,CA267170,TEC,Microenvironment,https://doi.org/10.1080/21623945.2024.2414919,Adipocyte,39415617,https://pubmed.ncbi.nlm.nih.gov/39415617,An improved <i>in vitro</i> 3T3-L1 adipocyte model of inflammation and insulin resistance,2024,"Inflammation, Insulin resistance, Adipocyte, 3T3-L1 cells, in vitro model","Ifeoluwa A Odeniyi, Bulbul Ahmed, Benjamin Anbiah, Grace Hester, Peter T Abraham, Elizabeth A Lipke, Michael W Greene","Tumor necrosis factor alpha (TNF-α)/hypoxia-treated 3T3-L1 adipocytes have been used to model inflamed and insulin-resistant adipose tissue: this study examines gaps in the model. We tested whether modulating TNF-α/hypoxia treatment time could reduce cell death while still inducing inflammation and insulin resistance. Adipocytes were treated with TNF-α (12 h or 24 h) and incubated in a hypoxic chamber for 24 h. To examine maintenance of the phenotype over time, glucose and FBS were added at 24 h post initiation of treatment, and the cells were maintained for an additional 48 h. Untreated adipocytes were used as a control. Viability, insulin resistance, and inflammation were assessed using Live/Dead staining, RT-qPCR, ELISA, and glucose uptake assays. Treatment for 12 h with TNF-α in the presence of hypoxia resulted in an increase in the percentage of live cells compared to 24 h treated cells. Importantly, insulin resistance and inflammation were still induced in the 12 h treated adipocytes: the expression of the insulin sensitive and inflammatory genes was decreased and increased, respectively. In 72 h treated adipocytes, no significant differences were found in the viability, glucose uptake or insulin-sensitive and inflammatory gene expression. This study provides a modified approach to in vitro odeling adipocyte inflammation and insulin resistance.        .",,,,,Open Access -PublicationView,CA274507,CSBC,"Computational Model Development, Drug Resistance/Sensitivity",https://doi.org/10.1038/s41540-024-00438-1,NPJ Syst Biol Appl,39349537,https://pubmed.ncbi.nlm.nih.gov/39349537,Spatial interactions modulate tumor growth and immune infiltration,2024,,"Sadegh Marzban, Sonal Srivastava, Sharon Kartika, Rafael Bravo, Rachel Safriel, Aidan Zarski, Alexander R A Anderson, Christine H Chung, Antonio L Amelio, Jeffrey West","Direct observation of tumor-immune interactions is unlikely in tumors with currently available technology, but computational simulations based on clinical data can provide insight to test hypotheses. It is hypothesized that patterns of collagen evolve as a mechanism of immune escape, but the exact nature of immune-collagen interactions is poorly understood. Spatial data quantifying collagen fiber alignment in squamous cell carcinomas indicates that late-stage disease is associated with highly aligned fibers. Our computational modeling framework discriminates between two hypotheses: immune cell migration that moves (1) parallel or (2) perpendicular to collagen fiber orientation. The modeling recapitulates immune-extracellular matrix interactions where collagen patterns provide immune protection, leading to an emergent inverse relationship between disease stage and immune coverage. Here, computational modeling provides important mechanistic insights by defining a kernel cell-cell interaction function that considers a spectrum of local (cell-scale) to global (tumor-scale) spatial interactions. Short-range interaction kernels provide a mechanism for tumor cell survival under conditions with strong Allee effects, while asymmetric tumor-immune interaction kernels lead to poor immune response. Thus, the length scale of tumor-immune interaction kernels drives tumor growth and infiltration.",,,,,Open Access -PublicationView,CA228963,PS-ON,Tumor-Immune,https://doi.org/10.1097/hc9.0000000000000533,Hepatol Commun,39330965,https://pubmed.ncbi.nlm.nih.gov/39330965,HCC spatial transcriptomic profiling reveals significant and potentially targetable cancer-endothelial interactions,2024,,"Chenyue Lu, Amaya Pankaj, Michael Raabe, Cole Nawrocki, Ann Liu, Nova Xu, Bidish K Patel, Matthew J Emmett, Avril K Coley, Cristina R Ferrone, Vikram Deshpande, Irun Bhan, Yujin Hoshida, David T Ting, Martin J Aryee, Joseph W Franses","Background: HCC is a highly vascular tumor, and many effective drug regimens target the tumor blood vessels. Prior bulk HCC subtyping data used bulk transcriptomes, which contained a mixture of parenchymal and stromal contributions. Methods: We utilized computational deconvolution and cell-cell interaction analyses to cell type-specific (tumor-enriched and vessel-enriched) spatial transcriptomic data collected from 41 resected HCC tissue specimens. Results: We report that the prior Hoshida bulk transcriptional subtyping schema is driven largely by an endothelial fraction, show an alternative tumor-specific schema has potential prognostic value, and use spatially paired ligand-receptor analyses to identify known and novel (LGALS9 tumor-HAVCR2 vessel) signaling relationships that drive HCC biology in a subtype-specific and potentially targetable manner. Conclusions: Our study leverages spatial gene expression profiling technologies to dissect HCC heterogeneity and identify heterogeneous signaling relationships between cancer cells and their endothelial cells. Future validation and expansion of these findings may validate novel cancer-endothelial cell interactions and related drug targets.",,,,GSE277104,Open Access -PublicationView,CA268069,CCBIR,"Immunotherapy, Microenvironment, Platform Development, Tumor-Immune",https://doi.org/10.1117/1.jbo.29.9.093511,J Biomed Opt,39364328,https://pubmed.ncbi.nlm.nih.gov/39364328,Machine learning-assisted mid-infrared spectrochemical fibrillar collagen imaging in clinical tissues,2024,"Cancer, second harmonic generation, Tumor Microenvironment, Machine Learning, Mid-infrared Spectral Imaging, Fibrillar Collagen Imaging","Wihan Adi, Bryan E Rubio Perez, Yuming Liu, Sydney Runkle, Kevin W Eliceiri, Filiz Yesilkoy","Significance: Label-free multimodal imaging methods that can provide complementary structural and chemical information from the same sample are critical for comprehensive tissue analyses. These methods are specifically needed to study the complex tumor-microenvironment where fibrillar collagen's architectural changes are associated with cancer progression. To address this need, we present a multimodal computational imaging method where mid-infrared spectral imaging (MIRSI) is employed with second harmonic generation (SHG) microscopy to identify fibrillar collagen in biological tissues. Aim: To demonstrate a multimodal approach where a morphology-specific contrast mechanism guides an MIRSI method to detect fibrillar collagen based on its chemical signatures. Approach: We trained a supervised machine learning (ML) model using SHG images as ground truth collagen labels to classify fibrillar collagen in biological tissues based on their mid-infrared hyperspectral images. Five human pancreatic tissue samples (sizes are in the order of millimeters) were imaged by both MIRSI and SHG microscopes. In total, 2.8 million MIRSI spectra were used to train a random forest (RF) model. The other 68 million spectra were used to validate the collagen images generated by the RF-MIRSI model in terms of collagen segmentation, orientation, and alignment. Results: Compared with the SHG ground truth, the generated RF-MIRSI collagen images achieved a high average boundary F -score (0.8 at 4-pixel thresholds) in the collagen distribution, high correlation (Pearson's R 0.82) in the collagen orientation, and similarly high correlation (Pearson's R 0.66) in the collagen alignment. Conclusions: We showed the potential of ML-aided label-free mid-infrared hyperspectral imaging for collagen fiber and tumor microenvironment analysis in tumor pathology samples.",,,,,Open Access -PublicationView,"CA274506, CA249799","TEC, CSBC","Metastasis, Platform Development, Tumor-Immune, Microenvironment, Drug Resistance/Sensitivity",https://doi.org/10.1073/pnas.2405257121,Proc Natl Acad Sci U S A,39374382,https://pubmed.ncbi.nlm.nih.gov/39374382,An engineered model of metastatic colonization of human bone marrow reveals breast cancer cell remodeling of the hematopoietic niche,2024,"Cancer, Tissue engineering, Hematopoiesis, Metastasis, Organoids","Ilaria Baldassarri, Daniel Naveed Tavakol, Pamela L Graney, Alan G Chramiec, Hanina Hibshoosh, Gordana Vunjak-Novakovic","Incomplete understanding of metastatic disease mechanisms continues to hinder effective treatment of cancer. Despite remarkable advancements toward the identification of druggable targets, treatment options for patients in remission following primary tumor resection remain limited. Bioengineered human tissue models of metastatic sites capable of recreating the physiologically relevant milieu of metastatic colonization may strengthen our grasp of cancer progression and contribute to the development of effective therapeutic strategies. We report the use of an engineered tissue model of human bone marrow (eBM) to identify microenvironmental cues regulating cancer cell proliferation and to investigate how triple-negative breast cancer (TNBC) cell lines influence hematopoiesis. Notably, individual stromal components of the bone marrow niche (osteoblasts, endothelial cells, and mesenchymal stem/stromal cells) were each critical for regulating tumor cell quiescence and proliferation in the three-dimensional eBM niche. We found that hematopoietic stem and progenitor cells (HSPCs) impacted TNBC cell growth and responded to cancer cell presence with a shift of HSPCs (CD34+CD38-) to downstream myeloid lineages (CD11b+CD14+). To account for tumor heterogeneity and show proof-of-concept ability for patient-specific studies, we demonstrate that patient-derived tumor organoids survive and proliferate in the eBM, resulting in distinct shifts in myelopoiesis that are similar to those observed for aggressively metastatic cell lines. We envision that this human tissue model will facilitate studies of niche-specific metastatic progression and individualized responses to treatment.",,,,,Open Access -PublicationView,CA214354,PS-ON,"Microenvironment, Tumor-Immune",https://doi.org/10.1039/d4bm00910j,Biomater Sci,39318195,https://pubmed.ncbi.nlm.nih.gov/39318195,Different leukocyte subsets are targeted by systemic and locoregional administration despite conserved nanomaterial characteristics optimal for lymph node delivery,2024,,"Paul A Archer, Alexander J Heiler, Alisyn R Bourque, Yunus Alapan, Susan N Thomas","Lymph nodes (LNs) house a large proportion of the body's leukocytes. Accordingly, engineered nanomaterials are increasingly developed to direct therapeutics to LNs to enhance their efficacy. Yet while lymphatic delivery of nanomaterials to LNs upon locoregional injection has been extensively evaluated, nanomaterial delivery to LN-localized leukocytes after intravenous administration has not been systematically explored nor benchmarked. In this work, a panel of inert, fluorescent nanoscale tracers and drug delivery vehicles were utilized to interrogate intravenous versus locoregionally administered nanomaterial access to LNs and leukocyte subsets therein. Hydrodynamic size and material effects on LN accumulation extents were similar between intravenous versus intradermal injection routes. Nanomaterial distribution to various LN leukocyte subsets differed substantially with injection route, however, in a manner not proportional to total LN accumulation. While intravenously administered nanomaterials accumulated in LNs lowly compared to systemic tissues, in sharp contrast to locoregional delivery, they exhibited size-dependent but material-independent access to immune cells within the LN parenchyma, which are not easily accessed with locoregional delivery.",,,,,Open Access -PublicationView,"CA220378, CA250481","PS-ON, CSBC","Heterogeneity, Evolution, Tumor-Immune",https://doi.org/10.3174/ajnr.a8357,AJNR Am J Neuroradiol,38782593,https://pubmed.ncbi.nlm.nih.gov/38782593,"Identification of a Single-Dose, Low-Flip-Angle-Based CBV Threshold for Fractional Tumor Burden Mapping in Recurrent Glioblastoma",2024,,"Aliya Anil, Ashley M Stokes, John P Karis, Laura C Bell, Jennifer Eschbacher, Kristofer Jennings, Melissa A Prah, Leland S Hu, Jerrold L Boxerman, Kathleen M Schmainda, C Chad Quarles","Background and purpose: DSC-MR imaging can be used to generate fractional tumor burden (FTB) maps via application of relative CBV thresholds to spatially differentiate glioblastoma recurrence from posttreatment radiation effects (PTRE). Image-localized histopathology was previously used to validate FTB maps derived from a reference DSC-MR imaging protocol by using preload, a moderate flip angle (MFA, 60°), and postprocessing leakage correction. Recently, a DSC-MR imaging protocol with a low flip angle (LFA, 30°) with no preload was shown to provide leakage-corrected relative CBV (rCBV) equivalent to the reference protocol. This study aimed to identify the rCBV thresholds for the LFA protocol that generate the most accurate FTB maps, concordant with those obtained from the reference MFA protocol. Materials and methods: Fifty-two patients with grade-IV glioblastoma who had prior surgical resection and received chemotherapy and radiation therapy were included in the study. Two sets of DSC-MR imaging data were collected sequentially first by using LFA protocol with no preload, which served as the preload for the subsequent MFA protocol. Standardized relative CBV maps (sRCBV) were obtained for each patient and coregistered with the anatomic postcontrast T1-weighted images. The reference MFA-based FTB maps were computed by using previously published sRCBV thresholds (1.0 and 1.56). A receiver operating characteristics (ROC) analysis was conducted to identify the optimal, voxelwise LFA sRCBV thresholds, and the sensitivity, specificity, and accuracy of the LFA-based FTB maps were computed with respect to the MFA-based reference. Results: The mean sRCBV values of tumors across patients exhibited strong agreement (concordance correlation coefficient = 0.99) between the 2 protocols. Using the ROC analysis, the optimal lower LFA threshold that accurately distinguishes PTRE from tumor recurrence was found to be 1.0 (sensitivity: 87.77%; specificity: 90.22%), equivalent to the ground truth. To identify aggressive tumor regions, the ROC analysis identified an upper LFA threshold of 1.37 (sensitivity: 90.87%; specificity: 91.10%) for the reference MFA threshold of 1.56. Conclusions: For LFA-based FTB maps, an sRCBV threshold of 1.0 and 1.37 can differentiate PTRE from recurrent tumors. FTB maps aid in surgical planning, guiding pathologic diagnosis and treatment strategies in the recurrent setting. This study further confirms the reliability of single-dose LFA-based DSC-MR imaging.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA256481,TEC,"Metastasis, Drug Resistance/Sensitivity, Platform Development",https://doi.org/10.1126/scitranslmed.adj5962,Sci Transl Med,38354228,https://pubmed.ncbi.nlm.nih.gov/38354228,Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization,2024,,"Jiajia Chen, Daniel J Laverty, Surabhi Talele, Ashwin Bale, Brett L Carlson, Kendra A Porath, Katrina K Bakken, Danielle M Burgenske, Paul A Decker, Rachael A Vaubel, Jeanette E Eckel-Passow, Rohit Bhargava, Zhenkun Lou, Petra Hamerlik, Brendan Harley, William F Elmquist, Zachary D Nagel, Shiv K Gupta, Jann N Sarkaria","ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G0-G1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53-mutant tumors but not in TP53-WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53-mutant, but not in TP53-WT, PDXs. In plasmid-based reporter assays, GBM43 (TP53-mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53 (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53-mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53-mutant cells to ATM inhibitor-mediated radiosensitization.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA209992,CSBC,"Microenvironment, Metastasis",https://doi.org/10.1016/j.molcel.2024.07.025,Mol Cell,39153475,https://pubmed.ncbi.nlm.nih.gov/39153475,Nuclear PKM2 binds pre-mRNA at folded G-quadruplexes and reveals their gene regulatory role,2024,"RNA-binding proteins, G-quadruplex, Pkm2, G4, Par-clip, Posttranscriptional Gene Regulation, Crosslinking And Immunoprecipitation","Dimitrios G Anastasakis, Maria Apostolidi, Khalid A Garman, Ahsan H Polash, Mubarak I Umar, Qingcai Meng, Jérémy Scutenaire, Jordan E Jarvis, Xiantao Wang, Astrid D Haase, Isaac Brownell, Jesse Rinehart, Markus Hafner","Nuclear localization of the metabolic enzyme PKM2 is widely observed in various cancer types. We identify nuclear PKM2 as a non-canonical RNA-binding protein (RBP) that specifically interacts with folded RNA G-quadruplex (rG4) structures in precursor mRNAs (pre-mRNAs). PKM2 occupancy at rG4s prevents the binding of repressive RBPs, such as HNRNPF, and promotes the expression of rG4-containing pre-mRNAs (the ""rG4ome""). We observe an upregulation of the rG4ome during epithelial-to-mesenchymal transition and a negative correlation of rG4 abundance with patient survival in different cancer types. By preventing the nuclear accumulation of PKM2, we could repress the rG4ome in triple-negative breast cancer cells and reduce migration and invasion of cancer cells in vitro and in xenograft mouse models. Our data suggest that the balance of folded and unfolded rG4s controlled by RBPs impacts gene expression during tumor progression.",Pending Annotation,Pending Annotation,Pending Annotation,GSE179817,Restricted Access -PublicationView,CA227136,TEC,"Microenvironment, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.ccell.2024.08.008,Cancer Cell,39255776,https://pubmed.ncbi.nlm.nih.gov/39255776,"Glioblastoma induces the recruitment and differentiation of dendritic-like ""hybrid"" neutrophils from skull bone marrow",2024,"T cells, Dendritic cells, Myeloid, Glioblastoma, Antigen-presenting cells, Mhc Class Ii, Tumor-associated Neutrophil, Skull Marrow","Meeki Lad, Angad S Beniwal, Saket Jain, Poojan Shukla, Venina Kalistratova, Jangham Jung, Sumedh S Shah, Garima Yagnik, Atul Saha, Ankita Sati, Husam Babikir, Alan T Nguyen, Sabraj Gill, Jennifer Rios, Jacob S Young, Austin Lui, Diana Salha, Aaron Diaz, Manish K Aghi","Tumor-associated neutrophil (TAN) effects on glioblastoma (GBM) biology remain under-characterized. We show here that neutrophils with dendritic features-including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate major histocompatibility complex (MHC)II-dependent T cell activation-accumulate intratumorally and suppress tumor growth in vivo. Trajectory analysis of patient TAN scRNA-seq identifies this ""hybrid"" dendritic-neutrophil phenotype as a polarization state that is distinct from canonical cytotoxic TANs, and which differentiates from local precursors. These hybrid-inducible immature neutrophils-which we identified in patient and murine glioblastomas-arise not from circulation, but from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a contributor of antitumoral myeloid antigen-presenting cells (APCs), including TANs, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow-such as intracalvarial AMD3100, whose survival-prolonging effect in GBM we report-present therapeutic potential.",Pending Annotation,Pending Annotation,Pending Annotation,GSE271618,Restricted Access -PublicationView,CA210180,PS-ON,"Heterogeneity, Microenvironment, Evolution",https://doi.org/10.1158/1078-0432.ccr-24-1849,Clin Cancer Res,39499201,https://pubmed.ncbi.nlm.nih.gov/39499201,Pilot Trial of Perampanel on Peritumoral Hyperexcitability in Newly Diagnosed High-grade Glioma. ,2024,,"Steven Tobochnik, Michael S Regan, Maria K C Dorotan, Dustine Reich, Emily Lapinskas, Md Amin Hossain, Sylwia Stopka, David M Meredith, Sandro Santagata, Melissa M Murphy, Omar Arnaout, Wenya Linda Bi, E Antonio Chiocca, Alexandra J Golby, Michael A Mooney, Timothy R Smith, Keith L Ligon, Patrick Y Wen, Nathalie Y R Agar, Jong Woo Lee","Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the targeted AMPA receptor antagonist perampanel on peritumoral hyperexcitability. An open-label trial was performed comparing perampanel with standard of care (SOC) in patients undergoing resection of newly diagnosed radiologic high-grade glioma. Perampanel was administered as a preoperative loading dose followed by maintenance therapy until progressive disease or up to 12 months. SOC treatment involved levetiracetam for 7 days or as clinically indicated. The primary outcome of hyperexcitability was defined by intraoperative electrocorticography high-frequency oscillation (HFO) rates. Seizure freedom and overall survival were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and correlative biomarkers were measured by mass spectrometry. HFO rates were similar between patients treated with perampanel and levetiracetam. The trial was terminated early after a planned interim analysis, and outcomes assessed in 11 patients (seven perampanel treated; four treated with SOC). Over a median 281 days of postenrollment follow-up, 27% of patients had seizures, including 14% maintained on perampanel and 50% treated with SOC. Overall survival in perampanel-treated patients was similar to that in a glioblastoma reference cohort. Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations. Glioma peritumoral glutamate concentrations correlated with high-gamma oscillation rates. Targeting glutamatergic activity with perampanel achieved similar electrocorticographic hyperexcitability levels as in levetiracetam-treated patients.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,"CA283114, CA238720",CSBC,"Computational Model Development, Drug Resistance/Sensitivity, Tumor-Immune",https://doi.org/10.1038/s41596-024-01076-x,Nat Protoc,39438697,https://pubmed.ncbi.nlm.nih.gov/39438697,Validation and quantification of peptide antigens presented on MHCs using SureQuant,2024,,"Owen Leddy, Yufei Cui, Ryuhjin Ahn, Lauren Stopfer, Elizabeth Choe, Do Hun Kim, Malte Roerden, Stefani Spranger, Bryan D Bryson, Forest M White","Vaccines and immunotherapies that target peptide-major histocompatibility complexes (peptide-MHCs) have the potential to address multiple unmet medical needs in cancer and infectious disease. Designing vaccines and immunotherapies to target peptide-MHCs requires accurate identification of target peptides in infected or cancerous cells or tissue, and may require absolute or relative quantification to identify abundant targets and measure changes in presentation under different treatment conditions. Internal standard parallel reaction monitoring (also known as 'SureQuant') can be used to validate and/or quantify MHC peptides previously identified by using untargeted methods such as data-dependent acquisition. SureQuant MHC has three main use cases: (i) conclusive confirmation of the identities of putative MHC peptides via comparison with an internal synthetic stable isotope labeled (SIL) peptide standard; (ii) accurate relative quantification by using pre-formed heavy isotope-labeled peptide-MHC complexes (hipMHCs) containing SIL peptides as internal controls for technical variation; and (iii) absolute quantification of each target peptide by using different amounts of hipMHCs loaded with synthetic peptides containing one, two or three SIL amino acids to provide an internal standard curve. Absolute quantification can help determine whether the abundance of a peptide-MHC is sufficient for certain therapeutic modalities. SureQuant MHC therefore provides unique advantages for immunologists seeking to confidently validate antigenic targets and understand the dynamics of the MHC repertoire. After synthetic standards are ordered (3-4 weeks), this protocol can be carried out in 3-4 days and is suitable for individuals with mass spectrometry experience who are comfortable with customizing instrument methods.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA261842,PS-ON,Drug Resistance/Sensitivity,https://doi.org/10.1007/s11538-024-01371-4,Bull Math Biol,39460828,https://pubmed.ncbi.nlm.nih.gov/39460828,"AMBER: A Modular Model for Tumor Growth, Vasculature and Radiation Response",2024,"Radiation Response, Agent-based Models, Hybrid Models, Tumor Modeling, Tumor Vascular Modeling","Louis V Kunz, Jesús J Bosque, Mohammad Nikmaneshi, Ibrahim Chamseddine, Lance L Munn, Jan Schuemann, Harald Paganetti, Alejandro Bertolet","Computational models of tumor growth are valuable for simulating the dynamics of cancer progression and treatment responses. In particular, agent-based models (ABMs) tracking individual agents and their interactions are useful for their flexibility and ability to model complex behaviors. However, ABMs have often been confined to small domains or, when scaled up, have neglected crucial aspects like vasculature. Additionally, the integration into tumor ABMs of precise radiation dose calculations using gold-standard Monte Carlo (MC) methods, crucial in contemporary radiotherapy, has been lacking. Here, we introduce AMBER, an Agent-based fraMework for radioBiological Effects in Radiotherapy that computationally models tumor growth and radiation responses. AMBER is based on a voxelized geometry, enabling realistic simulations at relevant pre-clinical scales by tracking temporally discrete states stepwise. Its hybrid approach, combining traditional ABM techniques with continuous spatiotemporal fields of key microenvironmental factors such as oxygen and vascular endothelial growth factor, facilitates the generation of realistic tortuous vascular trees. Moreover, AMBER is integrated with TOPAS, an MC-based particle transport algorithm that simulates heterogeneous radiation doses. The impact of radiation on tumor dynamics considers the microenvironmental factors that alter radiosensitivity, such as oxygen availability, providing a full coupling between the biological and physical aspects. Our results show that simulations with AMBER yield accurate tumor evolution and radiation treatment outcomes, consistent with established volumetric growth laws and radiobiological understanding. Thus, AMBER emerges as a promising tool for replicating essential features of tumor growth and radiation response, offering a modular design for future expansions to incorporate specific biological traits.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,"CA224012, CA209988","PDMC, CSBC","Heterogeneity, Microenvironment, Drug Resistance/Sensitivity, Experimental Model Development",https://doi.org/10.1002/path.6356,J Pathol,39435649,https://pubmed.ncbi.nlm.nih.gov/39435649,Suppression of dystroglycan function accompanies pancreatic acinar-to-ductal metaplasia and favours dysplasia development,2024,"Extracellular matrix, Basement membrane, Dysplasia, Precancer","Ge Huang, Luke Ternes, Christian Lanciault, Kevin MacPherson-Hawthorne, Young Hwan Chang, Rosalie C Sears, John L Muschler","The basement membrane (BM) is among the predominant microenvironmental factors of normal epithelia and of precancerous epithelial lesions. Evidence suggests that the BM functions not only as a barrier to tumour invasion but also as an active tumour-suppressing signalling substrate during premalignancy. However, the molecular foundations of such mechanisms have not been elucidated. Here we explore potential tumour-suppressing functions of the BM during precancer evolution, focusing on the expression and function of the extracellular matrix receptor dystroglycan in the pancreas and pancreatic disease. We show that the dystroglycan protein is highly expressed in the acinar compartment of the normal pancreas but lower in the ductal compartment. Moreover, there is a strong suppression of dystroglycan protein expression with acinar-to-ductal metaplasia in chronic pancreatitis and in all stages of pancreatic precancer and cancer evolution, from acinar-to-ductal metaplasia to dysplasia to adenocarcinoma. The conditional knockout of dystroglycan in the murine pancreas produced little evidence of developmental or functional deficiency. However, conditional deletion of dystroglycan expression in the context of oncogenic Kras expression led to a clear acceleration of pancreatic disease evolution, including accelerated dysplasia development and decreased survival. These data establish dystroglycan as a suppressor of pancreatic dysplasia development and one that is muted in chronic pancreatitis and at the earliest stages of oncogene-induced transformation. We conclude that dystroglycan is an important mediator of the tumour-suppressing functions of the BM during precancer evolution and that reduced dystroglycan function increases cancer risk, highlighting the dynamics of cell-BM interactions as important determinants of early cancer progression. © 2024 The Pathological Society of Great Britain and Ireland.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA244100,PS-ON,"Drug Resistance/Sensitivity, Tumor-Immune",https://doi.org/10.1007/s11538-024-01361-6,Bull Math Biol,39384633,https://pubmed.ncbi.nlm.nih.gov/39384633,Harnessing Flex Point Symmetry to Estimate Logistic Tumor Population Growth,2024,"Logistic function, Tumor Growth, Mathematical Oncology, Evolution Forecasting, Ghost Symmetry","Stefano Pasetto, Isha Harshe, Renee Brady-Nicholls, Robert A Gatenby, Heiko Enderling","The observed time evolution of a population is well approximated by a logistic growth function in many research fields, including oncology, ecology, chemistry, demography, economy, linguistics, and artificial neural networks. Initial growth is exponential, then decelerates as the population approaches its limit size, i.e., the carrying capacity. In mathematical oncology, the tumor carrying capacity has been postulated to be dynamically evolving as the tumor overcomes several evolutionary bottlenecks and, thus, to be patient specific. As the relative tumor-over-carrying capacity ratio may be predictive and prognostic for tumor growth and treatment response dynamics, it is paramount to estimate it from limited clinical data. We show that exploiting the logistic function's rotation symmetry can help estimate the population's growth rate and carry capacity from fewer data points than conventional regression approaches. We test this novel approach against published pan-cancer animal and human breast cancer data, achieving a 30% to 40% reduction in the time at which subsequent data collection is necessary to estimate the logistic growth rate and carrying capacity correctly. These results could improve tumor dynamics forecasting and augment the clinical decision-making process.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA274502,CSBC,"Heterogeneity, Computational Resource",https://doi.org/10.1080/14737140.2024.2417038,Expert Rev Anticancer Ther,39412140,https://pubmed.ncbi.nlm.nih.gov/39412140,Future investigative directions for novel therapeutic targets in head and neck cancer,2024,"Immunotherapy, Radiation Therapy, Pi3k Inhibitors, Hnscc, Breakthough Designation","Jacqueline P Nguyen, Liam C Woerner, Daniel E Johnson, Jennifer R Grandis","Areas covered: Here we describe novel agents, their mechanism(s) of action, preclinical results, and ongoing clinical trials in HNSCC. Expert opinion: Established therapeutic targets in HNSCC include EGFR (cetuximab) and PD-1 (pembrolizumab and nivolumab). Despite the detection of many other possible targets in HNSCC cell lines and patient tumors, no other therapies have successfully advanced to date. Identification of predictive biomarkers may guide the use of targeted agents and combination therapies. Clinical trials supported by strong preclinical data in relevant models are more likely to advance treatment options.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA224012,PDMC,"Heterogeneity, Drug Resistance/Sensitivity, Experimental Model Development",https://doi.org/10.1038/s41388-024-03196-w,Oncogene,39443726,https://pubmed.ncbi.nlm.nih.gov/39443726,KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development,2024,,"Samantha L Tinsley, Ella Rose D Chianis, Rebecca A Shelley, Gaganpreet K Mall, Alisha Dhiman, Garima Baral, Harish Kothandaraman, Mary C Thoma, Isabel A English, Colin J Daniel, Luis Carlos Sanjuan Acosta, Luis Solorio, Nadia Atallah Lanman, Marina Pasca di Magliano, Goutham Narla, Emily C Dykhuizen, Rosalie C Sears, Brittany L Allen-Petersen","Oncogenic mutations in KRAS are present in ~95% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are considered the initiating event of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. While it is well established that KRAS mutations drive the activation of oncogenic kinase cascades during pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (PP2A) has been implicated in suppressing KRAS-driven cellular transformation and low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRASG12D induces the expression of an endogenous inhibitor of PP2A activity, Cancerous Inhibitor of PP2A (CIP2A), and phosphorylation of the PP2A substrate, c-MYC. Consistent with these findings, KRASG12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56α, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation in vivo, knockout of B56α promoted KRASG12D tumorigenesis by accelerating acinar-to-ductal metaplasia (ADM) and the formation of PanIN lesions. The process of ADM was attenuated ex vivo in response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (SMAPs). Together, our results suggest that suppression of PP2A-B56α through KRAS signaling can promote the MYC-driven initiation of pancreatic tumorigenesis.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA274509,CSBC,"Immunotherapy, Computational Model Development",https://doi.org/10.1016/j.cell.2024.08.001,Cell,39181133,https://pubmed.ncbi.nlm.nih.gov/39181133,The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer drug resistance,2024,"DNA repair, DNA replication, Mitosis, Fragile sites, Genomic instability, micronuclei, Genome rearrangements, Fanconi Anemia, Chromothripsis, Ecdna","Justin L Engel, Xiao Zhang, Mingming Wu, Yan Wang, Jose Espejo Valle-Inclán, Qing Hu, Kidist S Woldehawariat, Mathijs A Sanders, Agata Smogorzewska, Jin Chen, Isidro Cortés-Ciriano, Roger S Lo, Peter Ly","Chromothripsis describes the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei. Although micronuclei accumulate DNA double-strand breaks and replication defects throughout interphase, how chromosomes undergo shattering remains unresolved. Using CRISPR-Cas9 screens, we identify a non-canonical role of the Fanconi anemia (FA) pathway as a driver of chromothripsis. Inactivation of the FA pathway suppresses chromosome shattering during mitosis without impacting interphase-associated defects within micronuclei. Mono-ubiquitination of FANCI-FANCD2 by the FA core complex promotes its mitotic engagement with under-replicated micronuclear chromosomes. The structure-selective SLX4-XPF-ERCC1 endonuclease subsequently induces large-scale nucleolytic cleavage of persistent DNA replication intermediates, which stimulates POLD3-dependent mitotic DNA synthesis to prime shattered fragments for reassembly in the ensuing cell cycle. Notably, FA-pathway-induced chromothripsis generates complex genomic rearrangements and extrachromosomal DNA that confer acquired resistance to anti-cancer therapies. Our findings demonstrate how pathological activation of a central DNA repair mechanism paradoxically triggers cancer genome evolution through chromothripsis.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA228963,PS-ON,Tumor-Immune,https://doi.org/10.1016/j.cell.2024.09.024,Cell,39383862,https://pubmed.ncbi.nlm.nih.gov/39383862,Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer,2024,"Pancreatic cancer, Tumor Microenvironment, Extracellular Vesicles, Cellular Plasticity, Cancer-associated Fibroblast, Spatial Transcriptomics, Repeat Rna","Eunae You, Patrick Danaher, Chenyue Lu, Siyu Sun, Luli Zou, Ildiko E Phillips, Alexandra S Rojas, Natalie I Ho, Yuhui Song, Michael J Raabe, Katherine H Xu, Peter M Richieri, Hao Li, Natalie Aston, Rebecca L Porter, Bidish K Patel, Linda T Nieman, Nathan Schurman, Briana M Hudson, Khrystyna North, Sarah E Church, Vikram Deshpande, Andrew S Liss, Tae K Kim, Yi Cui, Youngmi Kim, Benjamin D Greenbaum, Martin J Aryee, David T Ting","Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA227550,CSBC,"Heterogeneity, Drug Resistance/Sensitivity",https://doi.org/10.1016/j.cell.2024.08.013,Cell,39243764,https://pubmed.ncbi.nlm.nih.gov/39243764,Sex-dependent effects in the aged melanoma tumor microenvironment influence invasion and resistance to targeted therapy,2024,"Fibroblast, Melanoma, Aging, DNA damage, Senescence, Metastasis, Epigenetics, sex dimorphism, Tumor Microenvironment, Therapy Resistance, Sex Disparity","Yash Chhabra, Mitchell E Fane, Sneha Pramod, Laura Hüser, Daniel J Zabransky, Vania Wang, Agrani Dixit, Ruzhang Zhao, Edwin Kumah, Megan L Brezka, Kevin Truskowski, Asmita Nandi, Gloria E Marino-Bravante, Alexis E Carey, Naina Gour, Devon A Maranto, Murilo R Rocha, Elizabeth I Harper, Justin Ruiz, Evan J Lipson, Elizabeth M Jaffee, Kristin Bibee, Joel C Sunshine, Hongkai Ji, Ashani T Weeraratna","There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear. While biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Here, we show that skin fibroblasts undergo age-mediated, sex-dependent changes in their proliferation, senescence, ROS levels, and stress response. We find that aged male fibroblasts selectively drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Intrinsic aging in male fibroblasts mediated by EZH2 decline increases BMP2 secretion, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotypes and sensitizes melanoma cells to BRAF/MEK inhibition.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access diff --git a/annotations/oct_filepaths.csv b/annotations/oct_filepaths.csv deleted file mode 100644 index cbfa80b8..00000000 --- a/annotations/oct_filepaths.csv +++ /dev/null @@ -1,50 +0,0 @@ -File Paths,folderIdPublication -./output/output_oct/CA210184_publication.csv,syn32698226 -./output/output_oct/CA284090_publication.csv,syn53212987 -./output/output_oct/CA274499_publication.csv,syn43447156 -./output/output_oct/CA210173_publication.csv,syn32698222 -./output/output_oct/CA251443_publication.csv,syn35270499 -./output/output_oct/CA263001_publication.csv,syn43447092 -./output/output_oct/CA217514_publication.csv,syn35270557 -./output/output_oct/CA214297_publication.csv,syn32698320 -./output/output_oct/CA268072_publication.csv,syn35270530 -./output/output_oct/CA224013_publication.csv,syn35270551 -./output/output_oct/CA274502_publication.csv,syn43447174 -./output/output_oct/CA209975_publication.csv,syn32698159 -./output/output_oct/CA217376_publication.csv,syn32698091 -./output/output_oct/CA217378_publication.csv,syn32698086 -./output/output_oct/CA253540_publication.csv,syn32698462 -./output/output_oct/CA224012_publication.csv,syn35270567 -./output/output_oct/CA214354_publication.csv,syn32698033 -./output/output_oct/CA202177_publication.csv,syn32698236 -./output/output_oct/CA217377_publication.csv,syn32698266 -./output/output_oct/CA268084_publication.csv,syn52499923 -./output/output_oct/CA268083_publication.csv,syn35270525 -./output/output_oct/CA250040_publication.csv,syn32698315 -./output/output_oct/CA209992_publication.csv,syn32698178 -./output/output_oct/CA243075_publication.csv,syn32698431 -./output/output_oct/CA232137_publication.csv,syn32698071 -./output/output_oct/CA280849_publication.csv,syn53212962 -./output/output_oct/CA227550_publication.csv,syn32698064 -./output/output_oct/CA209971_publication.csv,syn32698166 -./output/output_oct/CA274506_publication.csv,syn32698150 -./output/output_oct/CA199315_publication.csv,syn32698278 -./output/output_oct/CA253553_publication.csv,syn32698451 -./output/output_oct/CA217450_publication.csv,syn32698096 -./output/output_oct/CA214300_publication.csv,syn32698367 -./output/output_oct/CA231978_publication.csv,syn32698100 -./output/output_oct/CA202123_publication.csv,syn32698231 -./output/output_oct/CA225088_publication.csv,syn32698012 -./output/output_oct/CA261694_publication.csv,syn35270536 -./output/output_oct/CA225566_publication.csv,syn32698345 -./output/output_oct/CA209988_publication.csv,syn32698270 -./output/output_oct/CA232517_publication.csv,syn32698413 -./output/output_oct/CA274511_publication.csv,syn53212942 -./output/output_oct/CA244100_publication.csv,syn32698334 -./output/output_oct/CA282451_publication.csv,syn53212972 -./output/output_oct/CA209891_publication.csv,syn32698008 -./output/output_oct/CA238720_publication.csv,syn32698104 -./output/output_oct/CA244107_publication.csv,syn32698325 -./output/output_oct/CA210152_publication.csv,syn32698024 -./output/output_oct/CA241927_publication.csv,syn32698394 -./output/output_oct/CA210181_publication.csv,syn32698212 diff --git a/annotations/oct_manifest.csv b/annotations/oct_manifest.csv deleted file mode 100755 index 6e8b0831..00000000 --- a/annotations/oct_manifest.csv +++ /dev/null @@ -1,58 +0,0 @@ -Component,Publication Grant Number,Publication Consortium Name,Publication Theme Name,Publication Doi,Publication Journal,Pubmed Id,Pubmed Url,Publication Title,Publication Year,Publication Keywords,Publication Authors,Publication Abstract,Publication Assay,Publication Tumor Type,Publication Tissue,Publication Dataset Alias,Publication Accessibility -PublicationView,CA274499,CSBC,"Oncogenic Stress, Metabolism",10.1016/j.celrep.2024.114775,Cell Rep,39305483,https://pubmed.ncbi.nlm.nih.gov/39305483,Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations,2024,"Oxidative phosphorylation, Glioma, PTEN, Mitochondrial electron transport chain, Multivariate Modeling, Synthetic Lethality, Cancer Metabolism, Cancer Therapies, Cp: Cancer, Cp: Metabolism, Metabolic State Vulnerabilities","Cara Abecunas, Audrey D Kidd, Ying Jiang, Hui Zong, Mohammad Fallahi-Sichani","Targeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges to identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tumor lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings via analysis of data from patient-derived tumors and pharmacological screens and by performing genetic and pharmacological experiments. Our analysis uncovers synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating the mechanisms underlying these relationships can inform the development of more precise and context-specific, metabolism-targeted cancer therapies.","Western Blotting, RNA Sequencing, Cell Culture",Pan-Cancer,Not Applicable,,Open Access -PublicationView,CA231978,CSBC,"Heterogeneity, Drug Resistance/Sensitivity",10.1016/j.coisb.2019.09.003,Curr Opin Syst Biol,37736115,https://pubmed.ncbi.nlm.nih.gov/37736115,Modeling genetic heterogeneity of drug response and resistance in cancer,2019,,"Teemu D Laajala, Travis Gerke, Svitlana Tyekucheva, James C Costello","Heterogeneity in tumors is recognized as a key contributor to drug resistance and spread of advanced disease, but deep characterization of genetic variation within tumors has only recently been quantifiable with the advancement of next generation sequencing and single cell technologies. These data have been essential in developing molecular models of how tumors develop, evolve, and respond to environmental changes, such as therapeutic intervention. A deeper understanding of tumor evolution has subsequently opened up new research efforts to develop mathematical models that account for evolutionary dynamics with the goal of predicting drug response and resistance in cancer. Here, we describe recent advances and limitations of how models of tumor evolution can impact treatment strategies for cancer patients.",,,,,Open Access -PublicationView,CA232517,TEC,"Microenvironment, Metastasis",10.1126/sciadv.adl4463,Sci Adv,38669327,https://pubmed.ncbi.nlm.nih.gov/38669327,The role of Piezo1 mechanotransduction in high-grade serous ovarian cancer: Insights from an in vitro model of collective detachment,2024,,"Hannah M Micek, Ning Yang, Mayuri Dutta, Lauren Rosenstock, Yicheng Ma, Caitlin Hielsberg, Molly McCord, Jacob Notbohm, Stephanie McGregor, Pamela K Kreeger","Slowing peritoneal spread in high-grade serous ovarian cancer (HGSOC) would improve patient prognosis and quality of life. HGSOC spreads when single cells and spheroids detach, float through the peritoneal fluid and take over new sites, with spheroids thought to be more aggressive than single cells. Using our in vitro model of spheroid collective detachment, we determine that increased substrate stiffness led to the detachment of more spheroids. We identified a mechanism where Piezo1 activity increased MMP-1/MMP-10, decreased collagen I and fibronectin, and increased spheroid detachment. Piezo1 expression was confirmed in omental masses from patients with stage III/IV HGSOC. Using OV90 and CRISPR-modified PIEZO1-/- OV90 in a mouse xenograft model, we determined that while both genotypes efficiently took over the omentum, loss of Piezo1 significantly decreased ascitic volume, tumor spheroids in the ascites, and the number of macroscopic tumors in the mesentery. These results support that slowing collective detachment may benefit patients and identify Piezo1 as a potential therapeutic target.",,,,,Open Access -PublicationView,CA232517,TEC,"Microenvironment, Metastasis",10.3390/cancers16081560,Cancers (Basel),38672642,https://pubmed.ncbi.nlm.nih.gov/38672642,A Perspective Review: Analyzing Collagen Alterations in Ovarian Cancer by High-Resolution Optical Microscopy,2024,"Clinical interventions, High-grade Serous Ovarian Cancer, Collagen Reorganization, Ecm Alterations","Kristal L Gant, Manish S Patankar, Paul J Campagnola","High-grade serous ovarian cancer (HGSOC) is the predominant subtype of ovarian cancer (OC), occurring in more than 80% of patients diagnosed with this malignancy. Histological and genetic analysis have confirmed the secretory epithelial of the fallopian tube (FT) as a major site of origin of HGSOC. Although there have been significant strides in our understanding of this disease, early stage detection and diagnosis are still rare. Current clinical imaging modalities lack the ability to detect early stage pathogenesis in the fallopian tubes and the ovaries. However, there are several microscopic imaging techniques used to analyze the structural modifications in the extracellular matrix (ECM) protein collagen in ex vivo FT and ovarian tissues that potentially can be modified to fit the clinical setting. In this perspective, we evaluate and compare the myriad of optical tools available to visualize these alterations and the invaluable insights these data provide on HGSOC initiation. We also discuss the clinical implications of these findings and how these data may help novel tools for early diagnosis of HGSOC.",,,,,Open Access -PublicationView,"CA253553, CA210181","PS-ON, CSBC","Microenvironment, Heterogeneity, Tumor-Immune, Metabolism",10.1172/jci.insight.165356,JCI Insight,38912586,https://pubmed.ncbi.nlm.nih.gov/38912586,Adjuvant COX inhibition augments STING signaling and cytolytic T cell infiltration in irradiated 4T1 tumors,2024,"Breast cancer, Inflammation, Oncology, adaptive immunity","Lisa A Ridnour, Robert Ys Cheng, Noemi Kedei, Veena Somasundaram, Dibyangana D Bhattacharyya, Debashree Basudhar, Adelaide L Wink, Abigail J Walke, Caleb Kim, William F Heinz, Elijah F Edmondson, Donna O Butcher, Andrew C Warner, Tiffany H Dorsey, Milind Pore, Robert J Kinders, Stanley Lipkowitz, Richard J Bryant, Jens Rittscher, Stephen Tc Wong, Stephen M Hewitt, Jenny C Chang, Aliaa Shalaby, Grace M Callagy, Sharon A Glynn, Stefan Ambs, Stephen K Anderson, Daniel W McVicar, Stephen J Lockett, David A Wink","Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts ""immune desert phenotypes"" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.",,,,"SRX24350068, SRX24350051, SRX24350113, SRX24350088, SRX24350086, SRX24350122, SRX24350126, SRX24350140, SRX24350120, SRX24350077, SRX24350142, SRX24350075, SRX24350134, SRX24350111, SRX24350117, SRX24350101, SRX24350066, SRX24350110, SRX24350136, SRX24350107, SRX24350062, SRX24350132, SRX24350090, SRX24350104, SRX24350095, SRX24350082, SRX24350093, SRX24350084, SRX24350124, SRX24350053, SRX24350102, SRX24350144, SRX24350108, SRX24350099, SRX24350070, SRX24350060, SRX24350098, SRX24350112, SRX24350054, SRX24350130, SRX24350116, SRX24350092, SRX24350071, SRX24350143, SRX24350097, SRX24350118, SRX24350121, SRX24350128, SRX24350129, SRX24350115, SRX24350056, SRX24350061, SRX24350057, SRX24350079, SRX24350067, SRX24350083, SRX24350100, SRX24350094, SRX24350125, SRX24350133, SRX24350105, SRX24350127, SRX24350089, SRX24350063, SRX24350138, SRP503680, SRX24350135, SRX24350114, SRX24350137, SRX24350131, SRX24350069, SRX24350123, SRX24350091, SRX24350109, SRX24350081, SRX24350085, SRX24350139, SRX24350080, SRX24350119, SRX24350058, SRX24350087, SRX24350076, SRX24350055, SRX24350103, SRX24350052, SRX24350059, SRX24350072, SRX24350073, SRX24350141, SRX24350074, SRX24350065, SRX24350078, SRX24350096, GSE264712, SRX24350106, SRX24350064",Open Access -PublicationView,CA199315,ICBP,"Microenvironment, Heterogeneity",10.1172/jci164227,J Clin Invest,39225101,https://pubmed.ncbi.nlm.nih.gov/39225101,Single-cell analysis of breast cancer metastasis reveals epithelial-mesenchymal plasticity signatures associated with poor outcomes,2024,"Breast cancer, Bioinformatics, Oncology","Juliane Winkler, Weilun Tan, Catherine Mm Diadhiou, Christopher S McGinnis, Aamna Abbasi, Saad Hasnain, Sophia Durney, Elena Atamaniuc, Daphne Superville, Leena Awni, Joyce V Lee, Johanna H Hinrichs, Patrick S Wagner, Namrata Singh, Marco Y Hein, Michael Borja, Angela M Detweiler, Su-Yang Liu, Ankitha Nanjaraj, Vaishnavi Sitarama, Hope S Rugo, Norma Neff, Zev J Gartner, Angela Oliveira Pisco, Andrei Goga, Spyros Darmanis, Zena Werb","Metastasis is the leading cause of cancer-related deaths. It is unclear how intratumor heterogeneity (ITH) contributes to metastasis and how metastatic cells adapt to distant tissue environments. The study of these adaptations is challenged by the limited access to patient material and a lack of experimental models that appropriately recapitulate ITH. To investigate metastatic cell adaptations and the contribution of ITH to metastasis, we analyzed single-cell transcriptomes of matched primary tumors and metastases from patient-derived xenograft models of breast cancer. We found profound transcriptional differences between the primary tumor and metastatic cells. Primary tumors upregulated several metabolic genes, whereas motility pathway genes were upregulated in micrometastases, and stress response signaling was upregulated during progression. Additionally, we identified primary tumor gene signatures that were associated with increased metastatic potential and correlated with patient outcomes. Immune-regulatory control pathways were enriched in poorly metastatic primary tumors, whereas genes involved in epithelial-mesenchymal transition were upregulated in highly metastatic tumors. We found that ITH was dominated by epithelial-mesenchymal plasticity (EMP), which presented as a dynamic continuum with intermediate EMP cell states characterized by specific genes such as CRYAB and S100A2. Elevated expression of an intermediate EMP signature correlated with worse patient outcomes. Our findings identified inhibition of the intermediate EMP cell state as a potential therapeutic target to block metastasis.",,,,,Open Access -PublicationView,CA210184,PS-ON,"Microenvironment, Metastasis, Metabolism",10.1126/sciadv.add0014,Sci Adv,36542704,https://pubmed.ncbi.nlm.nih.gov/36542704,Dissecting the recruitment and self-organization of αSMA-positive fibroblasts in the foreign body response,2022,,"Maria Parlani, Matthew L Bedell, Antonios G Mikos, Peter Friedl, Eleonora Dondossola","The foreign body response (FBR) is a clinically relevant issue that can cause malfunction of implanted medical devices by fibrotic encapsulation. Whereas inflammatory aspects of the FBR have been established, underlying fibroblast-dependent mechanisms remain unclear. We here combine multiphoton microscopy with ad hoc reporter mice expressing α-smooth muscle actin (αSMA) protein to determine the locoregional fibroblast dynamics, activation, and fibrotic encapsulation of polymeric materials. Fibroblasts invaded as individual cells and established a multicellular network, which transited to a two-compartment fibrotic response displaying an αSMA cold external capsule and a long-lasting, inner αSMA hot environment. The recruitment of fibroblasts and extent of fibrosis were only incompletely inhibited after depletion of macrophages, implicating coexistence of macrophage-dependent and macrophage-independent mediators. Furthermore, neither altering material type or porosity modulated αSMA+ cell recruitment and distribution. This identifies fibroblast activation and network formation toward a two-compartment FBR as a conserved, self-organizing process partially independent of macrophages.",,,,,Open Access -PublicationView,CA209992,CSBC,"Microenvironment, Metastasis",10.1002/mco2.174,MedComm (2020),36186235,https://pubmed.ncbi.nlm.nih.gov/36186235,The value of broad taxonomic comparisons in evolutionary medicine: Disease is not a trait but a state of a trait!,2022,"Pregnancy, Comparative Medicine, Evolutionary Medicine, Variational Traits","Mihaela Pavličev, Günter P Wagner","In this short paper, we argue that there is a fundamental connection between the medical sciences and evolutionary biology as both are sciences of biological variation. Medicine studies pathological variation among humans (and domestic animals in veterinary medicine) and evolutionary biology studies variation within and among species in general. A key principle of evolutionary biology is that genetic differences among species have arisen first from mutations originating within populations. This implies a mechanistic continuity between variation among individuals within a species and variation between species. This fact motivates research that seeks to leverage comparisons among species to unravel the genetic basis of human disease vulnerabilities. This view also implies that genetically caused diseases can be understood as extreme states of an underlying trait, that is, an axis of variation, rather than distinct traits, as often assumed in GWAS studies. We illustrate these points with a number of examples as diverse as anatomical birth defects, cranio-facial variation, preeclampsia and vulnerability to metastatic cancer.",,,,,Open Access -PublicationView,CA251443,TEC,"Microenvironment, Drug Resistance/Sensitivity, Platform Development",10.1038/s42003-022-04320-w,Commun Biol,36658332,https://pubmed.ncbi.nlm.nih.gov/36658332,"Biomechanical, biophysical and biochemical modulators of cytoskeletal remodelling and emergent stem cell lineage commitment",2023,,"Vina D L Putra, Kristopher A Kilian, Melissa L Knothe Tate","Across complex, multi-time and -length scale biological systems, redundancy confers robustness and resilience, enabling adaptation and increasing survival under dynamic environmental conditions; this review addresses ubiquitous effects of cytoskeletal remodelling, triggered by biomechanical, biophysical and biochemical cues, on stem cell mechanoadaptation and emergent lineage commitment. The cytoskeleton provides an adaptive structural scaffold to the cell, regulating the emergence of stem cell structure-function relationships during tissue neogenesis, both in prenatal development as well as postnatal healing. Identification and mapping of the mechanical cues conducive to cytoskeletal remodelling and cell adaptation may help to establish environmental contexts that can be used prospectively as translational design specifications to target tissue neogenesis for regenerative medicine. In this review, we summarize findings on cytoskeletal remodelling in the context of tissue neogenesis during early development and postnatal healing, and its relevance in guiding lineage commitment for targeted tissue regeneration. We highlight how cytoskeleton-targeting chemical agents modulate stem cell differentiation and govern responses to mechanical cues in stem cells' emerging form and function. We further review methods for spatiotemporal visualization and measurement of cytoskeletal remodelling, as well as its effects on the mechanical properties of cells, as a function of adaptation. Research in these areas may facilitate translation of stem cells' own healing potential and improve the design of materials, therapies, and devices for regenerative medicine.",,,,,Open Access -PublicationView,CA214354,PS-ON,"Microenvironment, Tumor-Immune",10.1063/1.5129937,APL Bioeng,32095735,https://pubmed.ncbi.nlm.nih.gov/32095735,From cellular to molecular mechanobiology,2020,,"Cheng Zhu, Cho-Yin Lee, Larry V McIntire","Mechanobiology at the cellular level is concerned with what phenotypes that cells exhibit to maintain homeostasis in their normal physiological mechanical environment, as well as what phenotypical changes that cells have to make when their environment is altered. Mechanobiology at the molecular level aims to understand the molecular underpinning of how cells sense, respond to, and adapt to mechanical cues in their environment. In this Perspective, we use our work inspired by and in collaboration with Professor Shu Chien as an example with which we connect the mechanobiology between the cellular and molecular levels. We discuss how physical forces acting on intracellular proteins may impact protein-protein interaction, change protein conformation, crosstalk with biochemical signaling molecules, induce mechanotransduction, and alter the cell structure and function.",,,,,Open Access -PublicationView,CA224013,PDMC,"Microenvironment, Heterogeneity",10.1016/j.celrep.2019.09.056,Cell Rep,31665640,https://pubmed.ncbi.nlm.nih.gov/31665640,Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism,2019,"Glutamine, Glutamine synthetase, Hexosamine, Nucleotide, Pancreatic cancer, nitrogen metabolism, K-ras, Α-ketoglutarate, Glutamate Ammonia Ligase","Alex J Bott, Jianliang Shen, Claudia Tonelli, Le Zhan, Nithya Sivaram, Ya-Ping Jiang, Xufen Yu, Vrushank Bhatt, Eric Chiles, Hua Zhong, Sara Maimouni, Weiwei Dai, Stephani Velasquez, Ji-An Pan, Nathiya Muthalagu, Jennifer Morton, Tracy G Anthony, Hui Feng, Wouter H Lamers, Daniel J Murphy, Jessie Yanxiang Guo, Jian Jin, Howard C Crawford, Lanjing Zhang, Eileen White, Richard Z Lin, Xiaoyang Su, David A Tuveson, Wei-Xing Zong","Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-ketoglutarate (aKG) to fuel the tricarboxylic acid (TCA) cycle. Supporting this notion, aKG supplementation can restore growth/survival of glutamine-deprived cells. However, pancreatic cancers are often poorly vascularized and limited in glutamine supply, in alignment with recent concerns on the significance of glutaminolysis in pancreatic cancer. Here, we show that aKG-mediated rescue of glutamine-deprived pancreatic ductal carcinoma (PDAC) cells requires glutamate ammonia ligase (GLUL), the enzyme responsible for de novo glutamine synthesis. GLUL-deficient PDAC cells are capable of the TCA cycle but defective in aKG-coupled glutamine biosynthesis and subsequent nitrogen anabolic processes. Importantly, GLUL expression is elevated in pancreatic cancer patient samples and in mouse PDAC models. GLUL ablation suppresses the development of KrasG12D-driven murine PDAC. Therefore, GLUL-mediated glutamine biosynthesis couples the TCA cycle with nitrogen anabolism and plays a critical role in PDAC.",,,,,Open Access -PublicationView,CA202177,PS-ON,"Microenvironment, Metastasis",10.1364/optica.6.000076,Optica,31984218,https://pubmed.ncbi.nlm.nih.gov/31984218,Scanless volumetric imaging by selective access multifocal multiphoton microscopy,2019,,"Yi Xue, Kalen P Berry, Josiah R Boivin, Christopher J Rowlands, Yu Takiguchi, Elly Nedivi, Peter T C So","Simultaneous, high-resolution imaging across a large number of synaptic and dendritic sites is critical for understanding how neurons receive and integrate signals. Yet, functional imaging that targets a large number of submicrometer-sized synaptic and dendritic locations poses significant technical challenges. We demonstrate a new parallelized approach to address such questions, increasing the signal-to-noise ratio by an order of magnitude compared to previous approaches. This selective access multifocal multiphoton microscopy uses a spatial light modulator to generate multifocal excitation in three dimensions (3D) and a Gaussian-Laguerre phase plate to simultaneously detect fluorescence from these spots throughout the volume. We test the performance of this system by simultaneously recording Ca2+ dynamics from cultured neurons at 98-118 locations distributed throughout a 3D volume. This is the first demonstration of 3D imaging in a ""single shot"" and permits synchronized monitoring of signal propagation across multiple different dendrites.",,,,,Open Access -PublicationView,CA217376,CSBC,"Microenvironment, Evolution, Epigenetics, Heterogeneity",10.3390/cancers14205008,Cancers (Basel),36291791,https://pubmed.ncbi.nlm.nih.gov/36291791,Comparative Evaluation of Tumor-Infiltrating Lymphocytes in Companion Animals: Immuno-Oncology as a Relevant Translational Model for Cancer Therapy,2022,"Canine, TILs, Neoplasia, Comparative Oncology","Christopher J Pinard, None None, Andrew Lagree, Fang-I Lu, Jonathan Klein, Michelle L Oblak, Roberto Salgado, Juan Carlos Pinto Cardenas, Barbara Brunetti, Luisa Vera Muscatello, Giuseppe Sarli, Maria Pia Foschini, Alexandros Hardas, Simon P Castillo, Khalid AbdulJabbar, Yinyin Yuan, David A Moore, William T Tran","Despite the important role of preclinical experiments to characterize tumor biology and molecular pathways, there are ongoing challenges to model the tumor microenvironment, specifically the dynamic interactions between tumor cells and immune infiltrates. Comprehensive models of host-tumor immune interactions will enhance the development of emerging treatment strategies, such as immunotherapies. Although in vitro and murine models are important for the early modelling of cancer and treatment-response mechanisms, comparative research studies involving veterinary oncology may bridge the translational pathway to human studies. The natural progression of several malignancies in animals exhibits similar pathogenesis to human cancers, and previous studies have shown a relevant and evaluable immune system. Veterinary oncologists working alongside oncologists and cancer researchers have the potential to advance discovery. Understanding the host-tumor-immune interactions can accelerate drug and biomarker discovery in a clinically relevant setting. This review presents discoveries in comparative immuno-oncology and implications to cancer therapy.",,,,,Open Access -PublicationView,"CA217514, CA214300","TEC, PDMC","Microenvironment, Epigenetics, Metastasis, Tumor-Immune",10.1016/j.gendis.2019.10.012,Genes Dis,33997167,https://pubmed.ncbi.nlm.nih.gov/33997167,Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance,2021,"Drug screening, Personalized Medicine, Chromatin Accessibility, Target Discovery, Patient-derived Organoids","Kuei-Ling Tung, Kai-Yuan Chen, Marcos Negrete, Tianyi Chen, Alexias Safi, Abed Alhalim Aljamal, Lingyun Song, Gregory E Crawford, Shengli Ding, David S Hsu, Xiling Shen","Colorectal cancer is a leading cause of cancer deaths. Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies. Here, we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin changes in response to oxaliplatin treatment. Integrated transcriptomic and chromatin accessibility analyses using ATAC-Seq and RNA-Seq identified a group of genes associated with significantly increased chromatin accessibility and upregulated gene expression. CRISPR/Cas9 silencing of fibroblast growth factor receptor 1 (FGFR1) and oxytocin receptor (OXTR) helped overcome oxaliplatin resistance. Similarly, treatment with oxaliplatin in combination with an FGFR1 inhibitor (PD166866) or an antagonist of OXTR (L-368,899) suppressed chemoresistant organoids. However, oxaliplatin treatment did not activate either FGFR1 or OXTR expression in another resistant organoid, suggesting that chromatin accessibility changes are patient-specific. The use of patient-derived cancer organoids in combination with transcriptomic and chromatin profiling may lead to precision treatments to overcome chemoresistance in colorectal cancer.",,,,,Open Access -PublicationView,CA210152,PS-ON,"Microenvironment, Metastasis",10.1016/j.isci.2023.105973,iScience,36756378,https://pubmed.ncbi.nlm.nih.gov/36756378,Regulation of DNA damage response by trimeric G-proteins,2023,"Molecular biology, Cell biology, Biological sciences","Amer Ali Abd El-Hafeez, Nina Sun, Anirban Chakraborty, Jason Ear, Suchismita Roy, Pranavi Chamarthi, Navin Rajapakse, Soumita Das, Kathryn E Luker, Tapas K Hazra, Gary D Luker, Pradipta Ghosh","Upon sensing DNA double-strand breaks (DSBs), eukaryotic cells either die or repair DSBs via one of the two competing pathways, i.e., non-homologous end-joining (NHEJ) or homologous recombination (HR). We show that cell fate after DSBs hinges on GIV/Girdin, a guanine nucleotide-exchange modulator of heterotrimeric Giα•βγ protein. GIV suppresses HR by binding and sequestering BRCA1, a key coordinator of multiple steps within the HR pathway, away from DSBs; it does so using a C-terminal motif that binds BRCA1's BRCT-modules via both phospho-dependent and -independent mechanisms. Using another non-overlapping C-terminal motif GIV binds and activates Gi and enhances the ""free"" Gβγ→PI-3-kinase→Akt pathway, which promotes survival and is known to suppress HR, favor NHEJ. Absence of GIV, or loss of either of its C-terminal motifs enhanced cell death upon genotoxic stress. Because GIV selectively binds other BRCT-containing proteins suggests that G-proteins may fine-tune sensing, repair, and survival after diverse types of DNA damage.",,,,,Open Access -PublicationView,CA214297,PS-ON,"Microenvironment, Metastasis",10.1038/s41698-019-0090-5,NPJ Precis Oncol,31341951,https://pubmed.ncbi.nlm.nih.gov/31341951,Blood-based monitoring identifies acquired and targetable driver HER2 mutations in endocrine-resistant metastatic breast cancer,2019,"Breast cancer, Cancer Genomics","Arielle J Medford, Taronish D Dubash, Dejan Juric, Laura Spring, Andrzej Niemierko, Neelima Vidula, Jeffrey Peppercorn, Steven Isakoff, Brittany A Reeves, Joseph A LiCausi, Benjamin Wesley, Giuliana Malvarosa, Megan Yuen, Ben S Wittner, Michael S Lawrence, A John Iafrate, Leif Ellisen, Beverly Moy, Mehmet Toner, Shyamala Maheswaran, Daniel A Haber, Aditya Bardia","Plasma genotyping identifies potentially actionable mutations at variable mutant allele frequencies, often admixed with multiple subclonal variants, highlighting the need for their clinical and functional validation. We prospectively monitored plasma genotypes in 143 women with endocrine-resistant metastatic breast cancer (MBC), identifying multiple novel mutations including HER2 mutations (8.4%), albeit at different frequencies highlighting clinical heterogeneity. To evaluate functional significance, we established ex vivo culture from circulating tumor cells (CTCs) from a patient with HER2-mutant MBC, which revealed resistance to multiple targeted therapies including endocrine and CDK 4/6 inhibitors, but high sensitivity to neratinib (IC50: 0.018 μM). Immunoblotting analysis of the HER2-mutant CTC culture line revealed high levels of HER2 expression at baseline were suppressed by neratinib, which also abrogated downstream signaling, highlighting oncogenic dependency with HER2 mutation. Furthermore, treatment of an index patient with HER2-mutant MBC with the irreversible HER2 inhibitor neratinib resulted in significant clinical response, with complete molecular resolution of two distinct clonal HER2 mutations, with persistence of other passenger subclones, confirming HER2 alteration as a driver mutation. Thus, driver HER2 mutant alleles that emerge during blood-based monitoring of endocrine-resistant MBC confer novel therapeutic vulnerability, and ex vivo expansion of viable CTCs from the blood circulation may broadly complement plasma-based mutational analysis in MBC.",,,,,Open Access -PublicationView,CA209988,CSBC,"Microenvironment, Heterogeneity, Drug Resistance/Sensitivity",10.1016/j.xcrm.2021.100267,Cell Rep Med,34095877,https://pubmed.ncbi.nlm.nih.gov/34095877,Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma,2021,"MEK, Kidney cancer, VEGFR, Dasatinib, Src, Combination Therapies, Cabozantinib, High Throughput Screen, Non-clear Cell Renal Cell Carcinoma, Cobimetinib","Hui-Wen Lue, Daniel S Derrick, Soumya Rao, Ahna Van Gaest, Larry Cheng, Jennifer Podolak, Samantha Lawson, Changhui Xue, Devin Garg, Ralph White, Christopher W Ryan, Justin M Drake, Anna Ritz, Laura M Heiser, George V Thomas","The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression in vivo. Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.",,,,"GSE171358, SRX10502049, SRX10502048, SRX10502045, SRX10502042, SRX10502046, SRX10502050, SRX10502051, SRX10502052, SRX10502053, SRX10502044, SRP313156, SRX10502047, SRX10502043",Open Access -PublicationView,CA202123,PS-ON,"Metastasis, Heterogeneity",10.1016/j.isci.2021.103252,iScience,34755092,https://pubmed.ncbi.nlm.nih.gov/34755092,A novel jamming phase diagram links tumor invasion to non-equilibrium phase separation,2021,"Cancer, Biophysics, Mechanobiology","Wenying Kang, Jacopo Ferruzzi, Catalina-Paula Spatarelu, Yu Long Han, Yasha Sharma, Stephan A Koehler, Jennifer A Mitchel, Adil Khan, James P Butler, Darren Roblyer, Muhammad H Zaman, Jin-Ah Park, Ming Guo, Zi Chen, Adrian F Pegoraro, Jeffrey J Fredberg","It is well established that the early malignant tumor invades surrounding extracellular matrix (ECM) in a manner that depends upon material properties of constituent cells, surrounding ECM, and their interactions. Recent studies have established the capacity of the invading tumor spheroids to evolve into coexistent solid-like, fluid-like, and gas-like phases. Using breast cancer cell lines invading into engineered ECM, here we show that the spheroid interior develops spatial and temporal heterogeneities in material phase which, depending upon cell type and matrix density, ultimately result in a variety of phase separation patterns at the invasive front. Using a computational approach, we further show that these patterns are captured by a novel jamming phase diagram. We suggest that non-equilibrium phase separation based upon jamming and unjamming transitions may provide a unifying physical picture to describe cellular migratory dynamics within, and invasion from, a tumor.",,,,,Open Access -PublicationView,CA274502,CSBC,"Heterogeneity, Computational Resource",10.3389/fonc.2023.1192208,Front Oncol,37384294,https://pubmed.ncbi.nlm.nih.gov/37384294,Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes,2023,"Drug resistance, Breast cancer, Drug Repurposing, Drug Repositioning, Primary Drug Resistance","Katharine Yu, Amrita Basu, Christina Yau, Denise M Wolf, Hani Goodarzi, Sourav Bandyopadhyay, James E Korkola, Gillian L Hirst, Smita Asare, Angela DeMichele, Nola Hylton, Douglas Yee, Laura Esserman, Laura van 't Veer, Marina Sirota","Introduction: Drug resistance is a major obstacle in cancer treatment and can involve a variety of different factors. Identifying effective therapies for drug resistant tumors is integral for improving patient outcomes. Methods: In this study, we applied a computational drug repositioning approach to identify potential agents to sensitize primary drug resistant breast cancers. We extracted drug resistance profiles from the I-SPY 2 TRIAL, a neoadjuvant trial for early stage breast cancer, by comparing gene expression profiles of responder and non-responder patients stratified into treatments within HR/HER2 receptor subtypes, yielding 17 treatment-subtype pairs. We then used a rank-based pattern-matching strategy to identify compounds in the Connectivity Map, a database of cell line derived drug perturbation profiles, that can reverse these signatures in a breast cancer cell line. We hypothesize that reversing these drug resistance signatures will sensitize tumors to treatment and prolong survival. Results: We found that few individual genes are shared among the drug resistance profiles of different agents. At the pathway level, however, we found enrichment of immune pathways in the responders in 8 treatments within the HR+HER2+, HR+HER2-, and HR-HER2- receptor subtypes. We also found enrichment of estrogen response pathways in the non-responders in 10 treatments primarily within the hormone receptor positive subtypes. Although most of our drug predictions are unique to treatment arms and receptor subtypes, our drug repositioning pipeline identified the estrogen receptor antagonist fulvestrant as a compound that can potentially reverse resistance across 13/17 of the treatments and receptor subtypes including HR+ and triple negative. While fulvestrant showed limited efficacy when tested in a panel of 5 paclitaxel resistant breast cancer cell lines, it did increase drug response in combination with paclitaxel in HCC-1937, a triple negative breast cancer cell line. Conclusion: We applied a computational drug repurposing approach to identify potential agents to sensitize drug resistant breast cancers in the I-SPY 2 TRIAL. We identified fulvestrant as a potential drug hit and showed that it increased response in a paclitaxel-resistant triple negative breast cancer cell line, HCC-1937, when treated in combination with paclitaxel.",,,,,Open Access -PublicationView,CA243075,CSBC,Drug Resistance/Sensitivity,10.1038/s41523-023-00530-5,NPJ Breast Cancer,37059742,https://pubmed.ncbi.nlm.nih.gov/37059742,Integration of clinical features and deep learning on pathology for the prediction of breast cancer recurrence assays and risk of recurrence,2023,,"Frederick M Howard, James Dolezal, Sara Kochanny, Galina Khramtsova, Jasmine Vickery, Andrew Srisuwananukorn, Anna Woodard, Nan Chen, Rita Nanda, Charles M Perou, Olufunmilayo I Olopade, Dezheng Huo, Alexander T Pearson","Gene expression-based recurrence assays are strongly recommended to guide the use of chemotherapy in hormone receptor-positive, HER2-negative breast cancer, but such testing is expensive, can contribute to delays in care, and may not be available in low-resource settings. Here, we describe the training and independent validation of a deep learning model that predicts recurrence assay result and risk of recurrence using both digital histology and clinical risk factors. We demonstrate that this approach outperforms an established clinical nomogram (area under the receiver operating characteristic curve of 0.83 versus 0.76 in an external validation cohort, p = 0.0005) and can identify a subset of patients with excellent prognoses who may not need further genomic testing.",,,,,Open Access -PublicationView,CA250040,PS-ON,Tumor-Immune,10.3389/fimmu.2024.1412513,Front Immunol,39253084,https://pubmed.ncbi.nlm.nih.gov/39253084,"Structure, function, and immunomodulation of the CD8 co-receptor",2024,"Monoclonal antibodies, T cell receptor, Immunomodulation, Major histocompatibility complex, T Cell Signaling, Chimeric Antigen Receptor, Cd8 Co-receptor","Shreyaa Srinivasan, Cheng Zhu, Andrew C McShan","Expressed on the surface of CD8+ T cells, the CD8 co-receptor is a key component of the T cells that contributes to antigen recognition, immune cell maturation, and immune cell signaling. While CD8 is widely recognized as a co-stimulatory molecule for conventional CD8+ αβ T cells, recent reports highlight its multifaceted role in both adaptive and innate immune responses. In this review, we discuss the utility of CD8 in relation to its immunomodulatory properties. We outline the unique structure and function of different CD8 domains (ectodomain, hinge, transmembrane, cytoplasmic tail) in the context of the distinct properties of CD8αα homodimers and CD8αβ heterodimers. We discuss CD8 features commonly used to construct chimeric antigen receptors for immunotherapy. We describe the molecular interactions of CD8 with classical MHC-I, non-classical MHCs, and Lck partners involved in T cell signaling. Engineered and naturally occurring CD8 mutations that alter immune responses are discussed. The applications of anti-CD8 monoclonal antibodies (mABs) that target CD8 are summarized. Finally, we examine the unique structure and function of several CD8/mAB complexes. Collectively, these findings reveal the promising immunomodulatory properties of CD8 and CD8 binding partners, not only to uncover basic immune system function, but to advance efforts towards translational research for targeted immunotherapy.",,,,,Open Access -PublicationView,CA232137,CSBC,"Microenvironment, Heterogeneity, Metabolism",10.46471/gigabyte.77,GigaByte,36949818,https://pubmed.ncbi.nlm.nih.gov/36949818,PhysiCOOL: A generalized framework for model Calibration and Optimization Of modeLing projects,2023,,"Inês G Gonçalves, David A Hormuth, Sandhya Prabhakaran, Caleb M Phillips, José Manuel García-Aznar","In silico models of biological systems are usually very complex and rely on a large number of parameters describing physical and biological properties that require validation. As such, parameter space exploration is an essential component of computational model development to fully characterize and validate simulation results. Experimental data may also be used to constrain parameter space (or enable model calibration) to enhance the biological relevance of model parameters. One widely used computational platform in the mathematical biology community is PhysiCell, which provides a standardized approach to agent-based models of biological phenomena at different time and spatial scales. Nonetheless, one limitation of PhysiCell is the lack of a generalized approach for parameter space exploration and calibration that can be run without high-performance computing access. Here, we present PhysiCOOL, an open-source Python library tailored to create standardized calibration and optimization routines for PhysiCell models.",,,,,Open Access -PublicationView,CA210173,PS-ON,"Microenvironment, Metastasis, Metabolism",10.1002/btm2.10403,Bioeng Transl Med,36925716,https://pubmed.ncbi.nlm.nih.gov/36925716,Vascular stiffening in aging females with a hypertension-induced HIF2A gain-of-function mutation,2023,"Hypertension, Hypoxia, Extracellular matrix, Pulmonary Arterial Hypertension, Hif, Arterial Stiffening, Hif2a, Systemic Arterial Stiffening","Eugenia Volkova, Linda Procell, Lingyang Kong, Lakshmi Santhanam, Sharon Gerecht","Pulmonary arterial hypertension (PAH) is more prevalent in females than males; the causes of this sex difference have not been adequately explored. Gain-of-function (GOF) mutations in hypoxia-inducible factor 2α (HIF2A) lead to PAH and thrombotic consequences in patients and mice. Additionally, multiple emerging studies suggest that elevated systemic arterial stiffening (SAS) occurs in PAH; this could have critical prognostic value. Here, we utilized a HIF2A GOF mouse model to determine how SAS can be used as a prognosticator in sex-divergent PAH. We analyzed survival, vascular mechanics, and vascular phenotypes in young adult (8-16 weeks) and middle age (9-12 months) Hif2a GOF mice. We find that Hif2a heterozygous (HT) female mice, but not Hif2a HT male mice, exhibit poor survival, SAS upon aging, and decreased ability to withstand repeated physiological strain. Hif2a HT female mice also display thickening of the adventitial intima and increased collagen I and collagen III in all layers of the thoracic aorta. Our findings demonstrate differing PAH progression in female and male Hif2a GOF mice. Specifically, alterations in extracellular matrix (ECM) content led to vascular stiffening in aged females, resulting in poor survival. Moreover, we show that SAS emerges early in mice with PAH by coupling studies of vascular mechanics and analyzing vascular structure and composition. Importantly, we present a model for assessing sex differences in hereditary PAH progression and sex-specific prognosis, proposing that aortic stiffening can be used to prognosticate future poor outcomes in PAH.",,,,,Open Access -PublicationView,CA217450,CSBC,"Microenvironment, Heterogeneity, Drug Resistance/Sensitivity",10.21037/tlcr-22-708,Transl Lung Cancer Res,37057106,https://pubmed.ncbi.nlm.nih.gov/37057106,Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review,2023,"Lung cancer, Clinical Trial, acquired resistance, Anaplastic Lymphoma Kinase (Alk)","Aakash Desai, Christine M Lovly","Background and objective: Anaplastic lymphoma kinase (ALK) rearrangements are detected in 3-7% of advanced non-small cell lung cancer (NSCLC). There are currently 5 U.S Food and Drug Administration (FDA)-approved ALK tyrosine kinase inhibitors (TKIs) for the treatment of patients with ALK-positive lung cancer in the advanced/metastatic disease setting. Despite these advances, most patients with ALK-positive lung cancer who are treated with ALK TKI therapy ultimately experience disease progression due to various mechanisms of drug resistance. In this review, we discuss strategies to address acquired therapeutic resistance to ALK inhibition, novel agents and combinatorial strategies in development for both on and off-target resistance, and some emerging approaches to prolong response to ALK inhibitors. Methods: We performed a search of peer-reviewed literature in the English language, conference abstracts, and trial registrations from the MEDLINE (Ovid), Embase (Elsevier), and CENTRAL (Cochrane Library) databases and major international oncology meetings up to August 2022. We then screened for studies describing interventions to overcome ALK resistance based on review of each title and abstract. Key content and findings: For patients with oligo-progression, treatment may include maintaining the same systemic treatment beyond progression while adding local therapies to progressing lesions. Strategies to combat ALK TKI resistance mediated by on-target resistance mechanisms include 4th generation TKIs (TPX-0131, NVL-655) and proteolysis-targeting chimeras (PROTACs) currently in development. While for those patients who develop tumor progression due to off-target (ALK independent) resistance, options may include combination therapies targeting ALK and other downstream or parallel pathways, novel antibody drug conjugates, or combinations of ALK inhibitors with chemotherapy and immunotherapy. Lastly, other potential strategies being explored in the clinic include circulating tumor DNA (ctDNA) surveillance to monitor for molecular mediators of drug resistance prior to frank progression on imaging studies and utilization of ALK TKIs in the adjuvant and neoadjuvant settings. Conclusions: Strategies to overcome resistance to currently available ALK inhibitors are urgently needed. Given the variety of resistance mechanisms, tailormade approaches are required for disease control.",,,,,Open Access -PublicationView,CA217376,CSBC,"Microenvironment, Evolution, Epigenetics, Heterogeneity",10.1038/s41586-024-07747-9,Nature,39112709,https://pubmed.ncbi.nlm.nih.gov/39112709,"The genomic landscape of 2,023 colorectal cancers",2024,,"Alex J Cornish, Andreas J Gruber, Ben Kinnersley, Daniel Chubb, Anna Frangou, Giulio Caravagna, Boris Noyvert, Eszter Lakatos, Henry M Wood, Steve Thorn, Richard Culliford, Claudia Arnedo-Pac, Jacob Househam, William Cross, Amit Sud, Philip Law, Maire Ni Leathlobhair, Aliah Hawari, Connor Woolley, Kitty Sherwood, Nathalie Feeley, Güler Gül, Juan Fernandez-Tajes, Luis Zapata, Ludmil B Alexandrov, Nirupa Murugaesu, Alona Sosinsky, Jonathan Mitchell, Nuria Lopez-Bigas, Philip Quirke, David N Church, Ian P M Tomlinson, Andrea Sottoriva, Trevor A Graham, David C Wedge, Richard S Houlston","Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.",,,,,Open Access -PublicationView,CA217378,CSBC,"Evolution, Heterogeneity, Drug Resistance/Sensitivity",10.1016/j.xpro.2021.100724,STAR Protoc,34401789,https://pubmed.ncbi.nlm.nih.gov/34401789,Quantitative analysis of m6A RNA modification by LC-MS,2021,"Molecular biology, Metabolism, Cell biology, Cell culture, Mass spectrometry, Chemistry","Lavina Mathur, Sunhee Jung, Cholsoon Jang, Gina Lee","N6-adenosine methylation (m6A) of messenger RNA (mRNA) plays key regulatory roles in gene expression. Accurate measurement of m6A levels is thus critical to understand its dynamic changes in various biological settings. Here, we provide a protocol to quantitate the levels of adenosine and m6A in cellular mRNAs. Using nuclease and phosphatase, we digest mRNA into nucleosides, which are subsequently quantified using liquid chromatography mass spectrometry. For complete details on the use and execution of this protocol, please refer to Cho et al. (2021).",,,,,Open Access -PublicationView,CA210173,PS-ON,"Microenvironment, Metastasis, Metabolism",10.1038/s41467-019-12412-1,Nat Commun,31649238,https://pubmed.ncbi.nlm.nih.gov/31649238,Fate-mapping post-hypoxic tumor cells reveals a ROS-resistant phenotype that promotes metastasis,2019,,"Inês Godet, Yu Jung Shin, Julia A Ju, I Chae Ye, Guannan Wang, Daniele M Gilkes","Hypoxia is known to be detrimental in cancer and contributes to its development. In this work, we present an approach to fate-map hypoxic cells in vivo in order to determine their cellular response to physiological O2 gradients as well as to quantify their contribution to metastatic spread. We demonstrate the ability of the system to fate-map hypoxic cells in 2D, and in 3D spheroids and organoids. We identify distinct gene expression patterns in cells that experienced intratumoral hypoxia in vivo compared to cells exposed to hypoxia in vitro. The intratumoral hypoxia gene-signature is a better prognostic indicator for distant metastasis-free survival. Post-hypoxic tumor cells have an ROS-resistant phenotype that provides a survival advantage in the bloodstream and promotes their ability to establish overt metastasis. Post-hypoxic cells retain an increase in the expression of a subset of hypoxia-inducible genes at the metastatic site, suggesting the possibility of a 'hypoxic memory.'",,,,"SRX3779354, SRX3779371, SRX5382138, SRX3779394, SRX3779388, SRX6779672, SRX3779355, SRX3779393, SRX3779396, SRX3779370, GSE111653, SRX3779338, SRX3779372, SRX6779675, SRX3779353, SRX3779345, SRX3779341, SRX3779376, SRX3779343, SRP219888, SRX3779336, SRP185979, SRX3779368, SRX6779674, SRX3779369, SRX3779344, SRX3779398, SRX3779386, SRX3779365, SRX3779382, SRX5382137, SRX3779347, SRX3779385, SRX3779383, SRX3779384, SRP134389, GSE136372, SRX3779337, SRX3779346, SRX3779361, SRX3779362, SRX3779350, SRX3779390, SRX3779373, SRX3779360, SRX3779358, SRX3779367, SRX3779381, SRX3779392, SRX3779375, SRX3779374, SRX3779380, SRX3779348, SRX3779391, GSE126609, SRX3779359, SRX3779387, SRX3779377, SRX3779357, SRX3779366, SRX6779673, SRX3779378, SRX3779339, SRX3779363, SRX3779349, SRX3779340, SRX3779395, SRX3779356, SRX3779351, SRX5382136, SRX3779342, SRX3779399, SRX3779352, SRX3779379, SRX3779364, SRX3779389, SRX3779397, SRX5382135",Open Access -PublicationView,CA274511,CSBC,Metastasis,10.1158/0008-5472.can-23-0046,Cancer Res,37409887,https://pubmed.ncbi.nlm.nih.gov/37409887,Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment,2023,,"Dhanya K Nambiar, Vignesh Viswanathan, Hongbin Cao, Weiruo Zhang, Li Guan, Manish Chamoli, Brittany Holmes, Christina Kong, Rachel Hildebrand, Amanda Jeanette Koong, Rie von Eyben, Sylvia Plevritis, Lingyin Li, Amato Giaccia, Edgar Engleman, Quynh Thu Le","The immune system plays a crucial role in the regulation of metastasis. Tumor cells systemically change immune functions to facilitate metastatic progression. Through this study, we deciphered how tumoral galectin-1 (Gal1) expression shapes the systemic immune environment to promote metastasis in head and neck cancer (HNC). In multiple preclinical models of HNC and lung cancer in immunogenic mice, Gal1 fostered the establishment of a premetastatic niche through polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), which altered the local microenvironment to support metastatic spread. RNA sequencing of MDSCs from premetastatic lungs in these models demonstrated the role of PMN-MDSCs in collagen and extracellular matrix remodeling in the premetastatic compartment. Gal1 promoted MDSC accumulation in the premetastatic niche through the NF-κB signaling axis, triggering enhanced CXCL2-mediated MDSC migration. Mechanistically, Gal1 sustained NF-κB activation in tumor cells by enhancing stimulator of interferon gene (STING) protein stability, leading to prolonged inflammation-driven MDSC expansion. These findings suggest an unexpected protumoral role of STING activation in metastatic progression and establish Gal1 as an endogenous-positive regulator of STING in advanced-stage cancers. Significance: Galectin-1 increases STING stability in cancer cells that activates NF-κB signaling and CXCL2 expression to promote MDSC trafficking, which stimulates the generation of a premetastatic niche and facilitates metastatic progression.",,,,,Open Access -PublicationView,CA209891,CSBC,"Evolution, Heterogeneity, Drug Resistance/Sensitivity",10.1038/s41467-024-52284-8,Nat Commun,39251601,https://pubmed.ncbi.nlm.nih.gov/39251601,MerlinS13 phosphorylation regulates meningioma Wnt signaling and magnetic resonance imaging features,2024,,"Charlotte D Eaton, Lauro Avalos, S John Liu, Zhenhong Chen, Naomi Zakimi, Tim Casey-Clyde, Paola Bisignano, Calixto-Hope G Lucas, Erica Stevenson, Abrar Choudhury, Harish N Vasudevan, Stephen T Magill, Jacob S Young, Nevan J Krogan, Javier E Villanueva-Meyer, Danielle L Swaney, David R Raleigh","Meningiomas are associated with inactivation of NF2/Merlin, but approximately one-third of meningiomas with favorable clinical outcomes retain Merlin expression. Biochemical mechanisms underlying Merlin-intact meningioma growth are incompletely understood, and non-invasive biomarkers that may be used to guide treatment de-escalation or imaging surveillance are lacking. Here, we use single-cell RNA sequencing, proximity-labeling proteomic mass spectrometry, mechanistic and functional approaches, and magnetic resonance imaging (MRI) across meningioma xenografts and patients to define biochemical mechanisms and an imaging biomarker that underlie Merlin-intact meningiomas. We find Merlin serine 13 (S13) dephosphorylation drives meningioma Wnt signaling and tumor growth by attenuating inhibitory interactions with β-catenin and activating the Wnt pathway. MRI analyses show Merlin-intact meningiomas with S13 phosphorylation and favorable clinical outcomes are associated with high apparent diffusion coefficient (ADC). These results define mechanisms underlying a potential imaging biomarker that could be used to guide treatment de-escalation or imaging surveillance for patients with Merlin-intact meningiomas.",,,,,Open Access -PublicationView,CA217376,CSBC,"Microenvironment, Evolution, Epigenetics, Heterogeneity",10.1038/s43018-024-00787-0,Nat Cancer,38997466,https://pubmed.ncbi.nlm.nih.gov/38997466,Tumor evolution metrics predict recurrence beyond 10 years in locally advanced prostate cancer,2024,,"Javier Fernandez-Mateos, George D Cresswell, Nicholas Trahearn, Katharine Webb, Chirine Sakr, Andrea Lampis, Christine Stuttle, Catherine M Corbishley, Vasilis Stavrinides, Luis Zapata, Inmaculada Spiteri, Timon Heide, Lewis Gallagher, Chela James, Daniele Ramazzotti, Annie Gao, Zsofia Kote-Jarai, Ahmet Acar, Lesley Truelove, Paula Proszek, Julia Murray, Alison Reid, Anna Wilkins, Michael Hubank, Ros Eeles, David Dearnaley, Andrea Sottoriva","Cancer evolution lays the groundwork for predictive oncology. Testing evolutionary metrics requires quantitative measurements in controlled clinical trials. We mapped genomic intratumor heterogeneity in locally advanced prostate cancer using 642 samples from 114 individuals enrolled in clinical trials with a 12-year median follow-up. We concomitantly assessed morphological heterogeneity using deep learning in 1,923 histological sections from 250 individuals. Genetic and morphological (Gleason) diversity were independent predictors of recurrence (hazard ratio (HR) = 3.12 and 95% confidence interval (95% CI) = 1.34-7.3; HR = 2.24 and 95% CI = 1.28-3.92). Combined, they identified a group with half the median time to recurrence. Spatial segregation of clones was also an independent marker of recurrence (HR = 2.3 and 95% CI = 1.11-4.8). We identified copy number changes associated with Gleason grade and found that chromosome 6p loss correlated with reduced immune infiltration. Matched profiling of relapse, decades after diagnosis, confirmed that genomic instability is a driving force in prostate cancer progression. This study shows that combining genomics with artificial intelligence-aided histopathology leads to the identification of clinical biomarkers of evolution.",,,,,Open Access -PublicationView,CA251443,TEC,"Microenvironment, Drug Resistance/Sensitivity, Platform Development",10.1016/j.mbplus.2024.100160,Matrix Biol Plus,39291079,https://pubmed.ncbi.nlm.nih.gov/39291079,The importance of matrix in cardiomyogenesis: Defined substrates for maturation and chamber specificity,2024,"Extracellular matrix proteins, Cardiomyocyte differentiation, Cardiomyocyte Maturation, Action Potential Morphology, Array Platform, Chamber Specification","Jake Ireland, Kristopher A Kilian","Human embryonic stem cell-derived cardiomyocytes (hESC-CM) are a promising source of cardiac cells for disease modelling and regenerative medicine. However, current protocols invariably lead to mixed population of cardiac cell types and often generate cells that resemble embryonic phenotypes. Here we developed a combinatorial approach to assess the importance of extracellular matrix proteins (ECMP) in directing the differentiation of cardiomyocytes from human embryonic stem cells (hESC). We did this by focusing on combinations of ECMP commonly found in the developing heart with a broad goal of identifying combinations that promote maturation and influence chamber specific differentiation. We formulated 63 unique ECMP combinations fabricated from collagen 1, collagen 3, collagen 4, fibronectin, laminin, and vitronectin, presented alone and in combinations, leading to the identification of specific ECMP combinations that promote hESC proliferation, pluripotency, and germ layer specification. When hESC were subjected to a differentiation protocol on the ECMP combinations, it revealed precise protein combinations that enhance differentiation as determined by the expression of cardiac progenitor markers kinase insert domain receptor (KDR) and mesoderm posterior transcription factor 1 (MESP1). High expression of cardiac troponin (cTnT) and the relative expression of myosin light chain isoforms (MLC2a and MLC2v) led to the identification of three surfaces that promote a mature cardiomyocyte phenotype. Action potential morphology was used to assess chamber specificity, which led to the identification of matrices that promote chamber-specific cardiomyocytes. This study provides a matrix-based approach to improve control over cardiomyocyte phenotypes during differentiation, with the scope for translation to cardiac laboratory models and for the generation of functional chamber specific cardiomyocytes for regenerative therapies.",,,,,Open Access -PublicationView,CA243075,CSBC,Drug Resistance/Sensitivity,10.3390/cancers16172942,Cancers (Basel),39272799,https://pubmed.ncbi.nlm.nih.gov/39272799,Agent-Based Modeling of Virtual Tumors Reveals the Critical Influence of Microenvironmental Complexity on Immunotherapy Efficacy,2024,"Bladder cancer, Cytotoxic T lymphocyte, Ordinary differential equation, Agent-based Model, Immune Checkpoint Inhibition, Fas/fas Ligand, Tumor Antigenicity, Perforin/granzyme","Yixuan Wang, Daniel R Bergman, Erica Trujillo, Anthony A Fernald, Lie Li, Alexander T Pearson, Randy F Sweis, Trachette L Jackson","Since the introduction of the first immune checkpoint inhibitor (ICI), immunotherapy has changed the landscape of molecular therapeutics for cancers. However, ICIs do not work equally well on all cancers and for all patients. There has been a growing interest in using mathematical and computational models to optimize clinical responses. Ordinary differential equations (ODEs) have been widely used for mechanistic modeling in immuno-oncology and immunotherapy. They allow rapid simulations of temporal changes in the cellular and molecular populations involved. Nonetheless, ODEs cannot describe the spatial structure in the tumor microenvironment or quantify the influence of spatially-dependent characteristics of tumor-immune dynamics. For these reasons, agent-based models (ABMs) have gained popularity because they can model more detailed phenotypic and spatial heterogeneity that better reflect the complexity seen in vivo. In the context of anti-PD-1 ICIs, we compare treatment outcomes simulated from an ODE model and an ABM to show the importance of including spatial components in computational models of cancer immunotherapy. We consider tumor cells of high and low antigenicity and two distinct cytotoxic T lymphocyte (CTL) killing mechanisms. The preferred mechanism differs based on the antigenicity of tumor cells. Our ABM reveals varied phenotypic shifts within the tumor and spatial organization of tumor and CTLs despite similarities in key immune parameters, initial simulation conditions, and early temporal trajectories of the cell populations.",,,,,Open Access -PublicationView,CA217378,CSBC,"Evolution, Heterogeneity, Drug Resistance/Sensitivity",10.1186/s12859-024-05926-z,BMC Bioinformatics,39294560,https://pubmed.ncbi.nlm.nih.gov/39294560,Leveraging gene correlations in single cell transcriptomic data,2024,"Melanoma, Gene Regulatory Network, Gene Co-expression Network, Single Cell Rna Sequencing, Gene–gene Correlation","Kai Silkwood, Emmanuel Dollinger, Joshua Gervin, Scott Atwood, Qing Nie, Arthur D Lander","Background: Many approaches have been developed to overcome technical noise in single cell RNA-sequencing (scRNAseq). As researchers dig deeper into data-looking for rare cell types, subtleties of cell states, and details of gene regulatory networks-there is a growing need for algorithms with controllable accuracy and fewer ad hoc parameters and thresholds. Impeding this goal is the fact that an appropriate null distribution for scRNAseq cannot simply be extracted from data in which ground truth about biological variation is unknown (i.e., usually). Results: We approach this problem analytically, assuming that scRNAseq data reflect only cell heterogeneity (what we seek to characterize), transcriptional noise (temporal fluctuations randomly distributed across cells), and sampling error (i.e., Poisson noise). We analyze scRNAseq data without normalization-a step that skews distributions, particularly for sparse data-and calculate p values associated with key statistics. We develop an improved method for selecting features for cell clustering and identifying gene-gene correlations, both positive and negative. Using simulated data, we show that this method, which we call BigSur (Basic Informatics and Gene Statistics from Unnormalized Reads), captures even weak yet significant correlation structures in scRNAseq data. Applying BigSur to data from a clonal human melanoma cell line, we identify thousands of correlations that, when clustered without supervision into gene communities, align with known cellular components and biological processes, and highlight potentially novel cell biological relationships. Conclusions: New insights into functionally relevant gene regulatory networks can be obtained using a statistically grounded approach to the identification of gene-gene correlations.",,,,,Open Access -PublicationView,"CA261694, CA268084","CCBIR, MetNet","Metastasis, Method/Assay Development, Epigenetics, Computational Model Development, Platform Development",10.7554/elife.97604,Elife,39331520,https://pubmed.ncbi.nlm.nih.gov/39331520,"Local volume concentration, packing domains, and scaling properties of chromatin",2024,"Theory, chromatin, None, Physics Of Living Systems, Sr-ev","Marcelo A Carignano, Martin Kroeger, Luay M Almassalha, Vasundhara Agrawal, Wing Shun Li, Emily M Pujadas-Liwag, Rikkert J Nap, Vadim Backman, Igal Szleifer","We propose the Self Returning Excluded Volume (SR-EV) model for the structure of chromatin based on stochastic rules and physical interactions. The SR-EV rules of return generate conformationally defined domains observed by single-cell imaging techniques. From nucleosome to chromosome scales, the model captures the overall chromatin organization as a corrugated system, with dense and dilute regions alternating in a manner that resembles the mixing of two disordered bi-continuous phases. This particular organizational topology is a consequence of the multiplicity of interactions and processes occurring in the nuclei, and mimicked by the proposed return rules. Single configuration properties and ensemble averages show a robust agreement between theoretical and experimental results including chromatin volume concentration, contact probability, packing domain identification and size characterization, and packing scaling behavior. Model and experimental results suggest that there is an inherent chromatin organization regardless of the cell character and resistant to an external forcing such as RAD21 degradation.",,,,,Open Access -PublicationView,CA244100,PS-ON,"Drug Resistance/Sensitivity, Tumor-Immune",10.1186/s13014-024-02514-6,Radiat Oncol,39272128,https://pubmed.ncbi.nlm.nih.gov/39272128,Spatially fractionated GRID radiation potentiates immune-mediated tumor control,2024,"mathematical model, Personalized Oncology, Spatially Fractionated Radiotherapy, Tumor Immune Interactions","Rebecca A Bekker, Nina Obertopp, Gage Redler, José Penagaricano, Jimmy J Caudell, Kosj Yamoah, Shari Pilon-Thomas, Eduardo G Moros, Heiko Enderling","Background: Tumor-immune interactions shape a developing tumor and its tumor immune microenvironment (TIME) resulting in either well-infiltrated, immunologically inflamed tumor beds, or immune deserts with low levels of infiltration. The pre-treatment immune make-up of the TIME is associated with treatment outcome; immunologically inflamed tumors generally exhibit better responses to radio- and immunotherapy than non-inflamed tumors. However, radiotherapy is known to induce opposing immunological consequences, resulting in both immunostimulatory and inhibitory responses. In fact, it is thought that the radiation-induced tumoricidal immune response is curtailed by subsequent applications of radiation. It is thus conceivable that spatially fractionated radiotherapy (SFRT), administered through GRID blocks (SFRT-GRID) or lattice radiotherapy to create areas of low or high dose exposure, may create protective reservoirs of the tumor immune microenvironment, thereby preserving anti-tumor immune responses that are pivotal for radiation success. Methods: We have developed an agent-based model (ABM) of tumor-immune interactions to investigate the immunological consequences and clinical outcomes after 2Gy×35 whole tumor radiation therapy (WTRT) and SFRT-GRID. The ABM is conceptually calibrated such that untreated tumors escape immune surveillance and grow to clinical detection. Individual ABM simulations are initialized from four distinct multiplex immunohistochemistry (mIHC) slides, and immune related parameter rates are generated using Latin Hypercube Sampling. Results: In silico simulations suggest that radiation-induced cancer cell death alone is insufficient to clear a tumor with WTRT. However, explicit consideration of radiation-induced anti-tumor immunity synergizes with radiation cytotoxicity to eradicate tumors. Similarly, SFRT-GRID is successful with radiation-induced anti-tumor immunity, and, for some pre-treatment TIME compositions and modeling parameters, SFRT-GRID might be superior to WTRT in providing tumor control. Conclusion: This study demonstrates the pivotal role of the radiation-induced anti-tumor immunity. Prolonged fractionated treatment schedules may counteract early immune recruitment, which may be protected by SFRT-facilitated immune reservoirs. Different biological responses and treatment outcomes are observed based on pre-treatment TIME composition and model parameters. A rigorous analysis and model calibration for different tumor types and immune infiltration states is required before any conclusions can be drawn for clinical translation.",,,,,Open Access -PublicationView,CA274499,CSBC,"Oncogenic Stress, Metabolism",10.1038/s44320-024-00064-3,Mol Syst Biol,39333715,https://pubmed.ncbi.nlm.nih.gov/39333715,Proteome-wide copy-number estimation from transcriptomics,2024,"CVB3, Tmt, Ccle, Swath, Pinferna","Andrew J Sweatt, Cameron D Griffiths, Sarah M Groves, B Bishal Paudel, Lixin Wang, David F Kashatus, Kevin A Janes","Protein copy numbers constrain systems-level properties of regulatory networks, but proportional proteomic data remain scarce compared to RNA-seq. We related mRNA to protein statistically using best-available data from quantitative proteomics and transcriptomics for 4366 genes in 369 cell lines. The approach starts with a protein's median copy number and hierarchically appends mRNA-protein and mRNA-mRNA dependencies to define an optimal gene-specific model linking mRNAs to protein. For dozens of cell lines and primary samples, these protein inferences from mRNA outmatch stringent null models, a count-based protein-abundance repository, empirical mRNA-to-protein ratios, and a proteogenomic DREAM challenge winner. The optimal mRNA-to-protein relationships capture biological processes along with hundreds of known protein-protein complexes, suggesting mechanistic relationships. We use the method to identify a viral-receptor abundance threshold for coxsackievirus B3 susceptibility from 1489 systems-biology infection models parameterized by protein inference. When applied to 796 RNA-seq profiles of breast cancer, inferred copy-number estimates collectively re-classify 26-29% of luminal tumors. By adopting a gene-centered perspective of mRNA-protein covariation across different biological contexts, we achieve accuracies comparable to the technical reproducibility of contemporary proteomics.",,,,,Open Access -PublicationView,"CA225566, CA253540","PS-ON, CSBC","Microenvironment, Heterogeneity, Drug Resistance/Sensitivity",10.1073/pnas.2403062121,Proc Natl Acad Sci U S A,39302966,https://pubmed.ncbi.nlm.nih.gov/39302966,Genetic variation drives cancer cell adaptation to ECM stiffness,2024,"Cancer, Mechanobiology, Ecm Stiffness, Mechanoadaptation","Ting-Ching Wang, Suchitaa Sawhney, Daylin Morgan, Richard L Bennett, Richa Rashmi, Marcos R Estecio, Amy Brock, Irtisha Singh, Charles F Baer, Jonathan D Licht, Tanmay P Lele","The progression of many solid tumors is accompanied by temporal and spatial changes in the stiffness of the extracellular matrix (ECM). Cancer cells adapt to soft and stiff ECM through mechanisms that are not fully understood. It is well known that there is significant genetic heterogeneity from cell to cell in tumors, but how ECM stiffness as a parameter might interact with that genetic variation is not known. Here, we employed experimental evolution to study the response of genetically variable and clonal populations of tumor cells to variable ECM stiffness. Proliferation rates of genetically variable populations cultured on soft ECM increased over a period of several weeks, whereas clonal populations did not evolve. Tracking of DNA barcoded cell lineages revealed that soft ECM consistently selected for the same few variants. These data provide evidence that ECM stiffness exerts natural selection on genetically variable tumor populations. Soft-selected cells were highly migratory, with enriched oncogenic signatures and unusual behaviors such as spreading and traction force generation on ECMs with stiffness as low as 1 kPa. Rho-regulated cell spreading was found to be the directly selected trait, with yes-associated protein 1 translocation to the nucleus mediating fitness on soft ECM. Overall, these data show that genetic variation can drive cancer cell adaptation to ECM stiffness.",,,,"SRX23623627, SRP489796, SRX23623621, SRX23623632, SRX23623631, SRX23623625, SRX23623633, SRX23623629, SRX23623626, SRX23623622, SRX23623630, SRX23623635, SRX23623634, GSE255829, SRX23623628, SRX23623624, SRX23623620, SRX23623623",Open Access -PublicationView,CA225088,CSBC,"Microenvironment, Drug Resistance/Sensitivity",10.1016/j.celrep.2024.114552,Cell Rep,39068660,https://pubmed.ncbi.nlm.nih.gov/39068660,ASCT2 is a major contributor to serine uptake in cancer cells,2024,"Diet, Breast cancer, Purine Biosynthesis, Cancer Metabolism, Amino Acid Uptake, Erα, Asct2, Slc1a5, Serine Transporter, Serine Starvation, Cp: Cancer","Kelly O Conger, Christopher Chidley, Mete Emir Ozgurses, Huiping Zhao, Yumi Kim, Svetlana E Semina, Philippa Burns, Vipin Rawat, Lina Lietuvninkas, Ryan Sheldon, Issam Ben-Sahra, Jonna Frasor, Peter K Sorger, Gina M DeNicola, Jonathan L Coloff","The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo, others are auxotrophic and therefore reliant on serine uptake. Importantly, despite several transporters being known to be capable of transporting serine, the transporters that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (SLC1A5) as a major contributor to serine uptake in cancer cells. ASCT2 is well known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that estrogen receptor α (ERα) promotes serine uptake by directly activating SLC1A5 transcription. Collectively, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target.",,,,,Open Access -PublicationView,CA224012,PDMC,"Drug Resistance/Sensitivity, Heterogeneity, Experimental Model Development",10.1158/0008-5472.can-23-1895,Cancer Res,38843355,https://pubmed.ncbi.nlm.nih.gov/38843355,IDH1 Inhibition Potentiates Chemotherapy Efficacy in Pancreatic Cancer,2024,,"Mehrdad Zarei, Omid Hajihassani, Jonathan J Hue, Alexander W Loftus, Hallie J Graor, Faith Nakazzi, Parnian Naji, Christina S Boutros, Vinayak Uppin, Ali Vaziri-Gohar, Akram S Shalaby, John M Asara, Luke D Rothermel, Jonathan R Brody, Jordan M Winter","Pancreatic ductal adenocarcinoma (PDAC) is associated with a 5-year overall survival rate of just 13%, and development of chemotherapy resistance is nearly universal. PDAC cells overexpress wild-type isocitrate dehydrogenase 1 (IDH1) that can enable them to overcome metabolic stress, suggesting it could represent a therapeutic target in PDAC. Here, we found that anti-IDH1 therapy enhanced the efficacy of conventional chemotherapeutics. Chemotherapy treatment induced reactive oxygen species (ROS) and increased tricarboxylic acid cycle activity in PDAC cells, along with the induction of wild-type IDH1 expression as a key resistance factor. IDH1 facilitated PDAC survival following chemotherapy treatment by supporting mitochondrial function and antioxidant defense to neutralize ROS through the generation of α-ketoglutarate and NADPH, respectively. Pharmacologic inhibition of wild-type IDH1 with ivosidenib synergized with conventional chemotherapeutics in vitro and potentiated the efficacy of subtherapeutic doses of these drugs in vivo in murine PDAC models. This promising treatment approach is translatable through available and safe oral inhibitors and provides the basis of an open and accruing clinical trial testing this combination (NCT05209074). Significance: Targeting IDH1 improves sensitivity to chemotherapy by suppressing mitochondrial function and inducing oxidative stress, supporting the potential of the combination as an effective strategy for treating pancreatic cancer.",,,,,Open Access -PublicationView,"CA274511, CA209971",CSBC,"Microenvironment, Metastasis, Tumor-Immune",10.1038/s41467-024-52394-3,Nat Commun,39289380,https://pubmed.ncbi.nlm.nih.gov/39289380,Basal-to-inflammatory transition and tumor resistance via crosstalk with a pro-inflammatory stromal niche,2024,,"Nancy Yanzhe Li, Weiruo Zhang, Daniel Haensel, Anna R Jussila, Cory Pan, Sadhana Gaddam, Sylvia K Plevritis, Anthony E Oro","Cancer-associated inflammation is a double-edged sword possessing both pro- and anti-tumor properties through ill-defined tumor-immune dynamics. While we previously identified a carcinoma tumor-intrinsic resistance pathway, basal-to-squamous cell carcinoma transition, here, employing a multipronged single-cell and spatial-omics approach, we identify an inflammation and therapy-enriched tumor state we term basal-to-inflammatory transition. Basal-to-inflammatory transition signature correlates with poor overall patient survival in many epithelial tumors. Basal-to-squamous cell carcinoma transition and basal-to-inflammatory transition occur in adjacent but distinct regions of a single tumor: basal-to-squamous cell carcinoma transition arises within the core tumor nodule, while basal-to-inflammatory transition emerges from a specialized inflammatory environment defined by a tumor-associated TREM1 myeloid signature. TREM1 myeloid-derived cytokines IL1 and OSM induce basal-to-inflammatory transition in vitro and in vivo through NF-κB, lowering sensitivity of patient basal cell carcinoma explant tumors to Smoothened inhibitor treatment. This work deepens our knowledge of the heterogeneous local tumor microenvironment and nominates basal-to-inflammatory transition as a drug-resistant but targetable tumor state driven by a specialized inflammatory microenvironment.",,,,,Open Access -PublicationView,CA209975,CSBC,"Drug Resistance/Sensitivity, Microenvironment, Metastasis, Tumor-Immune",10.1084/jem.20231193,J Exp Med,39321257,https://pubmed.ncbi.nlm.nih.gov/39321257,Precursor central memory versus effector cell fate and naïve CD4+ T cell heterogeneity,2024,,"Deeksha Deep, Herman Gudjonson, Chrysothemis C Brown, Samuel A Rose, Roshan Sharma, Yoselin A Paucar Iza, Seunghee Hong, Saskia Hemmers, Michail Schizas, Zhong-Min Wang, Yuezhou Chen, Duane R Wesemann, Virginia Pascual, Dana Pe'er, Alexander Y Rudensky","Upon antigenic stimulation, naïve CD4+ T cells can give rise to phenotypically distinct effector T helper cells and long-lived memory T cells. We computationally reconstructed the in vivo trajectory of CD4+ T cell differentiation during a type I inflammatory immune response and identified two distinct differentiation paths for effector and precursor central memory T cells arising directly from naïve CD4+ T cells. Unexpectedly, our studies revealed heterogeneity among naïve CD4+ T cells, which are typically considered homogeneous save for their diverse T cell receptor usage. Specifically, a previously unappreciated population of naïve CD4+ T cells sensing environmental type I IFN exhibited distinct activation thresholds, suggesting that naïve CD4+ T cell differentiation potential may be influenced by environmental cues. This population was expanded in human viral infection and type I IFN response-lined autoimmunity. Understanding the relevance of naïve T cell heterogeneity to beneficial and maladaptive T cell responses may have therapeutic implications for adoptive T cell therapies in cancer immunotherapy and vaccination.",,,,,Open Access -PublicationView,CA227550,CSBC,"Heterogeneity, Drug Resistance/Sensitivity",10.1016/j.celrep.2024.114721,Cell Rep,39255061,https://pubmed.ncbi.nlm.nih.gov/39255061,Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma,2024,"Melanoma, Aging, Angiogenesis, Fibroblasts, Exosomes, Extracellular Vesicles, Cd9, Cp: Cancer, Angioepoetin Ligand 2 (Angptl2)","Laura Hüser, Yash Chhabra, Olesia Gololobova, Vania Wang, Guanshu Liu, Agrani Dixit, Murilo Ramos Rocha, Elizabeth I Harper, Mitchell E Fane, Gloria E Marino-Bravante, Daniel J Zabransky, Kathy Q Cai, Jochen Utikal, Barbara S Slusher, Jeremy Walston, Evan J Lipson, Kenneth W Witwer, Ashani T Weeraratna","Advancing age is a negative prognostic factor for cutaneous melanoma. However, the role of extracellular vesicles (EVs) within the melanoma tumor microenvironment (TME) has remained unexplored in the context of aging. While the size and morphology of the EVs isolated from young vs. aged fibroblasts remained unaltered, the contents of the protein cargo were changed. Aging reduced the expression of the tetraspanin CD9 in both the dermal fibroblasts and released EVs. CD9 is a crucial regulator of EV cargo sorting. Modulating the CD9 expression in fibroblasts was sufficient to alter its levels in EVs. Mass spectrometry analysis of EVs released by CD9 knockdown (KD) vs. control cells revealed a significant increase in angiopoietin-like protein 2 (ANGPTL2), an angiogenesis promoter. Analysis of primary endothelial cells confirmed increased sprouting under CD9 KD conditions. Together, our data indicate that aged EVs play an important role in promoting a tumor-permissive microenvironment.",,,,,Open Access -PublicationView,"CA280849, CA244100",PS-ON,"Drug Resistance/Sensitivity, Microenvironment, Tumor-Immune, Computational Model Development",10.1038/s41416-024-02844-y,Br J Cancer,39261715,https://pubmed.ncbi.nlm.nih.gov/39261715,Fractionated photoimmunotherapy stimulates an anti-tumour immune response: an integrated mathematical and in vitro study,2024,,"Mohammad U Zahid, Matthew Waguespack, Rebecca C Harman, Eric M Kercher, Shubhankar Nath, Tayyaba Hasan, Imran Rizvi, Bryan Q Spring, Heiko Enderling","Background: Advanced epithelial ovarian cancer (EOC) has high recurrence rates due to disseminated initial disease presentation. Cytotoxic phototherapies, such as photodynamic therapy (PDT) and photoimmunotherapy (PIT, cell-targeted PDT), have the potential to treat disseminated malignancies due to safe intraperitoneal delivery. Methods: We use in vitro measurements of EOC tumour cell and T cell responses to chemotherapy, PDT, and epidermal growth factor receptor targeted PIT as inputs to a mathematical model of non-linear tumour and immune effector cell interaction. The model outputs were used to calculate how photoimmunotherapy could be utilised for tumour control. Results: In vitro measurements of PIT dose responses revealed that although low light doses (<10 J/cm2) lead to limited tumour cell killing they also increased proliferation of anti-tumour immune effector cells. Model simulations demonstrated that breaking up a larger light dose into multiple lower dose fractions (vis-à-vis fractionated radiotherapy) could be utilised to effect tumour control via stimulation of an anti-tumour immune response. Conclusions: There is promise for applying fractionated PIT in the setting of EOC. However, recommending specific fractionated PIT dosimetry and timing will require appropriate model calibration on tumour-immune interaction data in human patients and subsequent validation of model predictions in prospective clinical trials.",,,,,Open Access -PublicationView,CA241927,TEC,"Microenvironment, Metastasis",10.1016/j.xpro.2024.103266,STAR Protoc,39146187,https://pubmed.ncbi.nlm.nih.gov/39146187,Protocol for in vitro evaluation of effects of stiffness on patient-derived glioblastoma,2024,"Cancer, Tissue engineering, Material Sciences","Alireza Sohrabi, Stephanie K Seidlits","Glioblastoma (GBM) is the most common and lethal type of primary brain tumor. Physiologically, GBM cells experience a heterogeneous mechanical landscape. Here, we present an in vitro method to study the effects of tissue stiffness on patient-derived GBM that utilizes hyaluronic acid (HA)-based, mechanically tunable scaffolds for three-dimensional (3D) culture of patient-derived GBM spheroids. We describe steps to fabricate and characterize HA-based scaffolds, culture GBM spheroids within 3D hydrogel scaffolds, and prepare cultured cells for a variety of experimental assessments. For complete details on the use and execution of this protocol, please refer to Sohrabi et al.1.",,,,,Open Access -PublicationView,CA238720,CSBC,Drug Resistance/Sensitivity,10.1016/j.crmeth.2023.100483,Cell Rep Methods,37323574,https://pubmed.ncbi.nlm.nih.gov/37323574,Decrypting the potency of anti-cancer therapeutics by using mass spectrometry to quantify post-translational modifications,2023,,"Sophie A Herbst, Forest M White","In a recent issue of Science, Zecha et al.1 present decryptM, an approach aimed at defining the mechanisms of action of anti-cancer therapeutics through systems-level analysis of protein post-translational modifications (PTMs). By using a broad range of concentrations, decryptM generates drug response curves for each detected PTM, enabling identification of drug effects at different therapeutic doses.",,,,,Open Access -PublicationView,CA217377,CSBC,"Microenvironment, Drug Resistance/Sensitivity",10.1038/s41467-018-07478-2,Nat Commun,30487575,https://pubmed.ncbi.nlm.nih.gov/30487575,Selective expansion of myeloid and NK cells in humanized mice yields human-like vaccine responses,2018,,"Florian Douam, Carly G K Ziegler, Gabriela Hrebikova, Bruno Fant, Robert Leach, Lance Parsons, Wei Wang, Jenna M Gaska, Benjamin Y Winer, Brigitte Heller, Alex K Shalek, Alexander Ploss","Mice engrafted with components of a human immune system have become widely-used models for studying aspects of human immunity and disease. However, a defined methodology to objectively measure and compare the quality of the human immune response in different models is lacking. Here, by taking advantage of the highly immunogenic live-attenuated yellow fever virus vaccine YFV-17D, we provide an in-depth comparison of immune responses in human vaccinees, conventional humanized mice, and second generation humanized mice. We demonstrate that selective expansion of human myeloid and natural killer cells promotes transcriptomic responses akin to those of human vaccinees. These enhanced transcriptomic profiles correlate with the development of an antigen-specific cellular and humoral response to YFV-17D. Altogether, our approach provides a robust scoring of the quality of the human immune response in humanized mice and highlights a rational path towards developing better pre-clinical models for studying the human immune response and disease.",,,,"GSE119749, GSE119750, GSE119751",Open Access -PublicationView,CA232517,TEC,"Microenvironment, Metastasis",10.1007/978-1-0716-1956-8_6,Methods Mol Biol,34918289,https://pubmed.ncbi.nlm.nih.gov/34918289,Multispectral Staining and Analysis of Extracellular Matrix,2022,"Ovarian cancer, Stic, Serous Tubal Intra-epithelial Carcinoma","Carine M Renner, Mike R Visetsouk, Pamela K Kreeger, Kristyn S Masters","Multiplexed immunofluorescent (IF) techniques enable the detection of multiple antigens within the same sample and are therefore useful in situations where samples are rare or small in size. Similar to standard IF, multiplexed IF yields information on both the location and relative amount of detected antigens. While this method has been used primarily to detail cell phenotypes, we have recently adapted it to profile the extracellular matrix (ECM), which provides technical challenges due to autofluorescence and spatial overlap. This chapter details the planning, execution, optimization, and troubleshooting to use multiplexed IF to profile the ECM of human fallopian tube tissue.",,,,,Open Access -PublicationView,,,,10.1016/j.actbio.2024.08.026,Acta Biomater,39182805,https://pubmed.ncbi.nlm.nih.gov/39182805,Multiphoton excited polymerized biomimetic models of collagen fiber morphology to study single cell and collective migration dynamics in pancreatic cancer,2024,"Pancreatic cancer, Collective Migration, Single Cell Migration, Multiphoton Excited Fabrication, Collagen Fibers, Collagen Remodeling","Sophie Mancha, Meghan Horan, Ojaswi Pasachhe, Adib Keikhosravi, Kevin W Eliceiri, Kristina A Matkowskyj, Jacob Notbohm, Melissa C Skala, Paul J Campagnola","The respective roles of aligned collagen fiber morphology found in the extracellular matrix (ECM) of pancreatic cancer patients and cellular migration dynamics have been gaining attention because of their connection with increased aggressive phenotypes and poor prognosis. To better understand how collagen fiber morphology influences cell-matrix interactions associated with metastasis, we used Second Harmonic Generation (SHG) images from patient biopsies with Pancreatic ductal adenocarcinoma (PDAC) as models to fabricate collagen scaffolds to investigate processes associated with motility. Using the PDAC BxPC-3 metastatic cell line, we investigated single and collective cell dynamics on scaffolds of varying collagen alignment. Collective or clustered cells grown on the scaffolds with the highest collagen fiber alignment had increased E-cadherin expression and larger focal adhesion sites compared to single cells, consistent with metastatic behavior. Analysis of single cell motility revealed that the dynamics were characterized by random walk on all substrates. However, examining collective motility over different time points showed that the migration was super-diffusive and enhanced on highly aligned fibers, whereas it was hindered and sub-diffusive on un-patterned substrates. This was further supported by the more elongated morphology observed in collectively migrating cells on aligned collagen fibers. Overall, this approach allows the decoupling of single and collective cell behavior as a function of collagen alignment and shows the relative importance of collective cell behavior as well as fiber morphology in PDAC metastasis. We suggest these scaffolds can be used for further investigations of PDAC cell biology. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate, where aligned collagen has been associated with poor prognosis. Biomimetic models representing this architecture are needed to understand complex cellular interactions. The SHG image-based models based on stromal collagen from human biopsies afford the measurements of cell morphology, cadherin and focal adhesion expression as well as detailed motility dynamics. Using a metastatic cell line, we decoupled the roles of single cell and collective cell behavior as well as that arising from aligned collagen. Our data suggests that metastatic characteristics are enhanced by increased collagen alignment and that collective cell behavior is more relevant to metastatic processes. These scaffolds provide new insight in this disease and can be a platform for further experiments such as testing drug efficacy.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA261694,MetNet,"Method/Assay Development, Metastasis",10.1016/j.cell.2024.07.036,Cell,39178829,https://pubmed.ncbi.nlm.nih.gov/39178829,Multiphoton fluorescence microscopy for in vivo imaging,2024,,"Chris Xu, Maiken Nedergaard, Deborah J Fowell, Peter Friedl, Na Ji","Multiphoton fluorescence microscopy (MPFM) has been a game-changer for optical imaging, particularly for studying biological tissues deep within living organisms. MPFM overcomes the strong scattering of light in heterogeneous tissue by utilizing nonlinear excitation that confines fluorescence emission mostly to the microscope focal volume. This enables high-resolution imaging deep within intact tissue and has opened new avenues for structural and functional studies. MPFM has found widespread applications and has led to numerous scientific discoveries and insights into complex biological processes. Today, MPFM is an indispensable tool in many research communities. Its versatility and effectiveness make it a go-to technique for researchers investigating biological phenomena at the cellular and subcellular levels in their native environments. In this Review, the principles, implementations, capabilities, and limitations of MPFM are presented. Three application areas of MPFM, neuroscience, cancer biology, and immunology, are reviewed in detail and serve as examples for applying MPFM to biological research.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA268072,CCBIR,"Metastasis, Platform Development",10.1038/s41592-024-02413-4,Nat Methods,39261640,https://pubmed.ncbi.nlm.nih.gov/39261640,Navigate: an open-source platform for smart light-sheet microscopy,2024,,"Zach Marin, Xiaoding Wang, Dax W Collison, Conor McFadden, Jinlong Lin, Hazel M Borges, Bingying Chen, Dushyant Mehra, Qionghua Shen, Seweryn Gałecki, Stephan Daetwyler, Steven J Sheppard, Phu Thien, Baylee A Porter, Suzanne D Conzen, Douglas P Shepherd, Reto Fiolka, Kevin M Dean",No abstract available.,Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA263001,MetNet,"Metastasis, Microenvironment, Heterogeneity",10.1111/pcmr.13195,Pigment Cell Melanoma Res,39254030,https://pubmed.ncbi.nlm.nih.gov/39254030,MetFinder: A Tool for Automated Quantitation of Metastatic Burden in Histological Sections From Preclinical Models,2024,"Histopathology, Quantification, Preclinical Studies, Whole Slide Images, Murine Models, Deep Learning, Metastatic Burden","Alcida Karz, Nicolas Coudray, Erol Bayraktar, Kristyn Galbraith, George Jour, Arman Alberto Sorin Shadaloey, Nicole Eskow, Andrey Rubanov, Maya Navarro, Rana Moubarak, Gillian Baptiste, Grace Levinson, Valeria Mezzano, Mark Alu, Cynthia Loomis, Daniel Lima, Adam Rubens, Lucia Jilaveanu, Aristotelis Tsirigos, Eva Hernando","As efforts to study the mechanisms of melanoma metastasis and novel therapeutic approaches multiply, researchers need accurate, high-throughput methods to evaluate the effects on tumor burden resulting from specific interventions. We show that automated quantification of tumor content from whole slide images is a compelling solution to assess in vivo experiments. In order to increase the outflow of data collection from preclinical studies, we assembled a large dataset with annotations and trained a deep neural network for the quantitative analysis of melanoma tumor content on histopathological sections of murine models. After assessing its performance in segmenting these images, the tool obtained consistent results with an orthogonal method (bioluminescence) of measuring metastasis in an experimental setting. This AI-based algorithm, made freely available to academic laboratories through a web-interface called MetFinder, promises to become an asset for melanoma researchers and pathologists interested in accurate, quantitative assessment of metastasis burden.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA244107,PS-ON,"Microenvironment, Metastasis",10.1109/tmi.2024.3385644,IEEE Trans Med Imaging,38593022,https://pubmed.ncbi.nlm.nih.gov/38593022,Non-Invasive Imaging of Mechanical Properties of Cancers In Vivo Based on Transformations of the Eshelby's Tensor Using Compression Elastography,2024,,"Sharmin Majumder, Md Tauhidul Islam, Francesca Taraballi, Raffaella Righetti","Knowledge of the mechanical properties is of great clinical significance for diagnosis, prognosis and treatment of cancers. Recently, a new method based on Eshelby's theory to simultaneously assess Young's modulus (YM) and Poisson's ratio (PR) in tissues has been proposed. A significant limitation of this method is that accuracy of the reconstructed YM and PR is affected by the orientation/alignment of the tumor with the applied stress. In this paper, we propose a new method to reconstruct YM and PR in cancers that is invariant to the 3D orientation of the tumor with respect to the axis of applied stress. The novelty of the proposed method resides on the use of a tensor transformation to improve the robustness of Eshelby's theory and reconstruct YM and PR of tumors with high accuracy and in realistic experimental conditions. The method is validated using finite element simulations and controlled experiments using phantoms with known mechanical properties. The in vivo feasibility of the developed method is demonstrated in an orthotopic mouse model of breast cancer. Our results show that the proposed technique can estimate the YM and PR with overall accuracy of (97.06 ± 2.42) % under all tested tumor orientations. Animal experimental data demonstrate the potential of the proposed methodology in vivo. The proposed method can significantly expand the range of applicability of the Eshelby's theory to tumors and provide new means to accurately image and quantify mechanical parameters of cancers in clinical conditions.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,"CA284090, CA268083","CCBIR, MetNet","Microenvironment, Method/Assay Development, Metastasis, Tumor Progression",10.1083/jcb.202311002,J Cell Biol,39320351,https://pubmed.ncbi.nlm.nih.gov/39320351,Claudin 7 suppresses invasion and metastasis through repression of a smooth muscle actin program,2024,,"Junior J West, Rosela Golloshi, Chae Yun Cho, Yuqian Wang, Parker Stevenson, Genevieve Stein-O'Brien, Elana J Fertig, Andrew J Ewald","Metastasis initiates when cancer cells escape from the primary tumor, which requires changes to intercellular junctions. Claudins are transmembrane proteins that form the tight junction, and their expression is reduced in aggressive breast tumors. However, claudins' roles during breast cancer metastasis remain unclear. We used gain- and loss-of-function genetics in organoids isolated from murine breast cancer models to establish that Cldn7 suppresses invasion and metastasis. Transcriptomic analysis revealed that Cldn7 knockdown induced smooth muscle actin (SMA)-related genes and a broader mesenchymal phenotype. We validated our results in human cell lines, fresh human tumor tissue, bulk RNA-seq, and public single-cell RNA-seq data. We consistently observed an inverse relationship between Cldn7 expression and expression of SMA-related genes. Furthermore, knockdown and overexpression of SMA-related genes demonstrated that they promote breast cancer invasion. Our data reveal that Cldn7 suppresses breast cancer invasion and metastasis through negative regulation of SMA-related and mesenchymal gene expression.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA282451,TEC,"Microenvironment, Experimental Model Development",10.1126/science.adi1563,Science,38060634,https://pubmed.ncbi.nlm.nih.gov/38060634,Self-enhancing sono-inks enable deep-penetration acoustic volumetric printing,2023,,"Xiao Kuang, Qiangzhou Rong, Saud Belal, Tri Vu, Alice M López López, Nanchao Wang, Mehmet Onur Arıcan, Carlos Ezio Garciamendez-Mijares, Maomao Chen, Junjie Yao, Yu Shrike Zhang","Volumetric printing, an emerging additive manufacturing technique, builds objects with enhanced printing speed and surface quality by forgoing the stepwise ink-renewal step. Existing volumetric printing techniques almost exclusively rely on light energy to trigger photopolymerization in transparent inks, limiting material choices and build sizes. We report a self-enhancing sonicated ink (or sono-ink) design and corresponding focused-ultrasound writing technique for deep-penetration acoustic volumetric printing (DAVP). We used experiments and acoustic modeling to study the frequency and scanning rate-dependent acoustic printing behaviors. DAVP achieves the key features of low acoustic streaming, rapid sonothermal polymerization, and large printing depth, enabling the printing of volumetric hydrogels and nanocomposites with various shapes regardless of their optical properties. DAVP also allows printing at centimeter depths through biological tissues, paving the way toward minimally invasive medicine.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA227550,CSBC,"Heterogeneity, Drug Resistance/Sensitivity",10.1158/0008-5472.can-24-0086,Cancer Res,38330147,https://pubmed.ncbi.nlm.nih.gov/38330147,Fibroblasts in the Aged Pancreas Drive Pancreatic Cancer Progression,2024,,"Daniel J Zabransky, Yash Chhabra, Mitchell E Fane, Emma Kartalia, James M Leatherman, Laura Hüser, Jacquelyn W Zimmerman, Daniel Delitto, Song Han, Todd D Armstrong, Soren Charmsaz, Samantha Guinn, Sneha Pramod, Elizabeth D Thompson, Steven J Hughes, Jennifer O'Connell, Josephine M Egan, Elizabeth M Jaffee, Ashani T Weeraratna","Pancreatic cancer is more prevalent in older individuals and often carries a poorer prognosis for them. The relationship between the microenvironment and pancreatic cancer is multifactorial, and age-related changes in nonmalignant cells in the tumor microenvironment may play a key role in promoting cancer aggressiveness. Because fibroblasts have profound impacts on pancreatic cancer progression, we investigated whether age-related changes in pancreatic fibroblasts influence cancer growth and metastasis. Proteomics analysis revealed that aged fibroblasts secrete different factors than young fibroblasts, including increased growth/differentiation factor 15 (GDF-15). Treating young mice with GDF-15 enhanced tumor growth, whereas aged GDF-15 knockout mice showed reduced tumor growth. GDF-15 activated AKT, rendering tumors sensitive to AKT inhibition in an aged but not young microenvironment. These data provide evidence for how aging alters pancreatic fibroblasts and promotes tumor progression, providing potential therapeutic targets and avenues for studying pancreatic cancer while accounting for the effects of aging. Significance: Aged pancreatic fibroblasts secrete GDF-15 and activate AKT signaling to promote pancreatic cancer growth, highlighting the critical role of aging-mediated changes in the pancreatic cancer microenvironment in driving tumor progression. See related commentary by Isaacson et al., p. 1185.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA268083,CCBIR,"Microenvironment, Method/Assay Development, Metastasis",10.1158/0008-5472.can-23-3082,Cancer Res,38959339,https://pubmed.ncbi.nlm.nih.gov/38959339,E-Cadherin Induces Serine Synthesis to Support Progression and Metastasis of Breast Cancer,2024,,"Geonhui Lee, Claudia Wong, Anna Cho, Junior J West, Ashleigh J Crawford, Gabriella C Russo, Bishwa R Si, Jungwoo Kim, Lauren Hoffner, Cholsoon Jang, Moonjung Jung, Robert D Leone, Konstantinos Konstantopoulos, Andrew J Ewald, Denis Wirtz, Sangmoo Jeong","The loss of E-cadherin, an epithelial cell adhesion molecule, has been implicated in metastasis by mediating the epithelial-mesenchymal transition, which promotes invasion and migration of cancer cells. However, recent studies have demonstrated that E-cadherin supports the survival and proliferation of metastatic cancer cells. Here, we identified a metabolic role for E-cadherin in breast cancer by upregulating the de novo serine synthesis pathway (SSP). The upregulated SSP provided metabolic precursors for biosynthesis and resistance to oxidative stress, enabling E-cadherin+ breast cancer cells to achieve faster tumor growth and enhanced metastases. Inhibition of phosphoglycerate dehydrogenase, a rate-limiting enzyme in the SSP, significantly and specifically hampered proliferation of E-cadherin+ breast cancer cells and rendered them vulnerable to oxidative stress, inhibiting their metastatic potential. These findings reveal that E-cadherin reprograms cellular metabolism, promoting tumor growth and metastasis of breast cancers. Significance: E-Cadherin promotes the progression and metastasis of breast cancer by upregulating the de novo serine synthesis pathway, offering promising targets for inhibiting tumor growth and metastasis in E-cadherin-expressing tumors.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access -PublicationView,CA274506,CSBC,"Microenvironment, Tumor-Immune",10.1097/cmr.0000000000000974,Melanoma Res,38640504,https://pubmed.ncbi.nlm.nih.gov/38640504,Pseudoprogression in a patient with metastatic melanoma treated with PD-1 and LAG-3 inhibition,2024,,"Lawrence W Wu, Jacqueline J Tao, Diana McDonnell, Benjamin Izar","Pseudoprogression encapsulates a process of temporary radiographic growth followed by subsequent regression of metastatic melanoma lesions in response to immune checkpoint blockade (ICB), such as the combination of anti-programmed cell death protein 1 (PD-1) and anticytotoxic T-lymphocyte-associated antigen 4 therapy. This occurs in approximately 5-10% of ICB-treated patients, but has not yet been described in the context of novel combination therapies. Here, we report a case of an 89-year-old patient with metastatic melanoma to the liver, lung and lymph nodes, who underwent treatment with Opdualag (combining anti-PD-1 nivolumab and anti-lymphocyte-activation gene 3 relatlimab ICBs), and developed pseudoprogression after two cycles of therapy. The patient experienced a radiographic increase in liver metastatic lesion size, but was found to have a subsequent reduction in these lesions. The patient has been on therapy for 18 months without evidence of disease progression and continues to be clinically well-appearing.",Pending Annotation,Pending Annotation,Pending Annotation,,Restricted Access