Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 88,878 bioRxiv papers from 381,072 authors.
Most downloaded bioRxiv papers, since beginning of last month
in category cancer biology
3,051 results found. For more information, click each entry to expand.
159 downloads cancer biology
Cysteine is required for maintaining cellular redox homeostasis in both normal and transformed cells. Deprivation of cysteine induces the iron-dependent form of cell death known as ferroptosis; however, the metabolic consequences of cysteine starvation beyond impairment of glutathione synthesis are uncharacterized. Here, we find that cystine starvation promotes ferroptosis not only through the inhibition of glutathione (GSH) synthesis, but also through the accumulation of glutamate. Surprisingly, we find that glutamate-cysteine ligase catalytic subunit (GCLC) prevents glutamate accumulation through the generation of alternative γ-glutamyl peptides. Further, inhibition of GCLC accelerates ferroptosis under cystine starvation in a GSH-independent manner. These results indicate that GCLC has an additional, non-canonical role in the protection against ferroptosis to maintain glutamate homeostasis under cystine starvation. ### Competing Interest Statement The authors declare no competing financial interests. I.S.H. is a consultant for Ono Pharma USA, who had no role in funding or design of this study.
157 downloads cancer biology
Loredana Spoerri, Crystal A. Tonnessen-Murray, Gency Gunasingh, David S Hill, Kimberley A. Beaumont, Russell J Jurek, Gilles Vanwalleghem, Mitchell E. Fane, Sheena M. Daignault, Nicholas Matigian, Ethan K. Scott, Aaron G. Smith, Samantha J. Stehbens, Helmut Schaider, Wolfgang Weninger, Brian Gabrielli, Nikolas K. Haass
Phenotypic and functional cancer cell heterogeneity limits the efficacy of targeted and immuno-therapies. The transcription factor MITF is known to regulate melanoma cell plasticity and, consequently, response to drugs. However, the underlying mechanisms of this phenomenon remain incompletely understood. Here, we show that MITF levels control functional melanoma cell heterogeneity by fine-tuning the ability to contract the extracellular matrix, the maturation of focal adhesions and ROCK-mediated melanoma cell contractility. Modulation of MITF expression alters extracellular matrix organization, melanoma cell morphology and solid stress in three-dimensional melanoma spheroids, thereby accounting for spatial differences in cell cycle dynamics. Together, our data identify MITF as a master regulator of the melanoma micro-architecture and point towards novel targeting strategies for cancer cell heterogeneity. ### Competing Interest Statement The authors have declared no competing interest.
156 downloads cancer biology
UCSC Xena is a visual exploration resource for both public and private omics data, supported through the web-based Xena Browser and multiple turn-key Xena Hubs. This unique archecture allows researchers to view their own data securely, using private Xena Hubs, simultaneously visualizing large public cancer genomics datasets, including TCGA and the GDC. Data integration occurs only within the Xena Browser, keeping private data private. Xena supports virtually any functional genomics data, including SNVs, INDELs, large structural variants, CNV, expression, DNA methylation, ATAC-seq signals, and phenotypic annotations. Browser features include the Visual Spreadsheet, survival analyses, powerful filtering and subgrouping, statistical analyses, genomic signatures, and bookmarks. Xena differentiates itself from other genomics tools, including its predecessor, the UCSC Cancer Genomics Browser, by its ability to easily and securely view public and private data, its high performance, its broad data type support, and many unique features.
156 downloads cancer biology
Cell lines are key tools for preclinical cancer research, but it remains unclear how well they represent patient tumor samples. Identifying cell line models that best represent the features of particular tumor samples, as well as tumor types that lack in vitro model representation, remain important challenges. Gene expression has been shown to provide rich information that can be used to identify tumor subtypes, as well as predict the genetic dependencies and chemical vulnerabilities of cell lines. However, direct comparisons of tumor and cell line transcriptional profiles are complicated by systematic differences, such as the presence of immune and stromal cells in tumor samples and differences in the cancer-type composition of cell line and tumor expression datasets. To address these challenges, we developed an unsupervised alignment method (Celligner) and applied it to integrate several large-scale cell line and tumor RNA-Seq datasets. While our method aligns the majority of cell lines with tumor samples of the same cancer type, it also reveals large differences in tumor/cell line similarity across disease types. Furthermore, Celligner identifies a distinct group of several hundred cell lines from diverse lineages that present a more mesenchymal and undifferentiated transcriptional state and which exhibit distinct chemical and genetic dependencies. This method could thus be used to guide the selection of cell lines that more closely resemble patient tumors and improve the clinical translation of insights gained from cell line models.
156 downloads cancer biology
Advanced age is strongly correlated with both increased cancer incidence and general immune decline. The immune tumor microenvironment (ITME) has been established as an important prognostic of both therapeutic efficacy and overall patient survival. Thus, age-related immune decline is an important consideration for the treatment of a large subset of cancer patients. Current studies of aging-related immune alterations are predominantly performed on non-cancerous tissue, requiring additional study into the effects of age on tumor immune infiltration. We leverage large scale transcriptional data sets from The Cancer Genome Atlas and the Genotype-Tissue Expression project to distinguish normal age-related immune alterations from age-related changes in tumor immune infiltration. We demonstrate that while there is overlap between the normal immune aging phenotype and that of the ITME, there are several changes in immune cell abundance that are specific to the ITME, particularly in T cell, NK cell, and Macrophage populations. These results suggest that aged immune cells are more susceptible to tumor suppression of cytotoxic immune cell infiltration and activity than normal tissues, which creates an unfavorable ITME in older patients in excess of normal immune decline with age and may inform the application of existing and emerging immunotherapies for this large population of patients. We additionally identify that age-related increases in tumor mutational burden are associated with decreased DNA methylation and increased expression of the immune checkpoint genes PDL1, CD80, and LAG3 which may have implications for therapeutic application of immune checkpoint blockade in older patients. ### Competing Interest Statement The authors have declared no competing interest.
153 downloads cancer biology
Thale K. Olsen, Jörg Otte, Shenglin Mei, Polina Kameneva, Åsa Björklund, Emil Kryukov, Ziyi Hou, Anna Johansson, Erik Sundström, Tommy Martinsson, Susanne Fransson, John Inge Johnsen, Per Kogner, Igor Adameyko, Peter V. Kharchenko, Ninib Baryawno
Neuroblastoma is a heterogeneous embryonal malignancy and the most deadly tumor of childhood, although a minor subset may show spontaneous differentiation. It arises from the multipotent neural crest lineage during development. Some of this multipotency is retained in neuroblastoma, which can give rise to both adrenergic and mesenchymal tumor cells. The mechanisms enabling such dual fates are unknown, but likely help neuroblastoma to evade existing therapies. To understand neuroblastoma plasticity, we analyzed patient tumors using single-cell transcriptomics. In addition to the heterogeneous adrenergic and mesenchymal populations, we identify a subpopulation of malignant cells resembling Schwann cell precursors (SCPs). This SCP-like population connects the adrenergic and mesenchymal compartments through transitions structurally reminiscent of the SCP cell-fate decision fork that occurs during normal development. While the directionality of such transitions in neuroblastoma remains to be established, this finding expands the potential reservoirs of malignant cells, and suggests intratumoral plasticity mechanisms relevant for therapeutic resistance and relapse. ### Competing Interest Statement P.V.K serves on the Scientific Advisory Board to Celsius Therapeutics, Inc. Other authors declare no conflict of interest.
152 downloads cancer biology
The MLL-AF9 fusion protein occurring as a result of t(9;11) translocation gives rise to pediatric and adult acute leukemias of distinct lineages, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and mixed phenotype acute leukemia (MPAL). The mechanisms underlying how this same fusion protein results in diverse leukemia phenotypes among different individuals is not well understood. Given emerging evidence from genome-wide association studies (GWAS) that genetic risk factors contribute to MLL-rearranged leukemogenesis, here we tested the impact of genetic background on survival and phenotype of a well-characterized Mll-AF9 knockin mouse model. We crossed this model to five distinct inbred strains (129, A/J, C57BL/6, NOD, CAST), and tested their F1 hybrid progeny for dominant genetic effects on Mll-AF9 phenotypes. We discovered that genetic background altered peripheral blood composition, with Mll-AF9 CAST F1 demonstrating significantly increased B lymphocyte frequency while the remainder of the strains exhibited myeloid-biased hematopoiesis, similar to the parental line. Genetic background also impacted overall survival, with Mll-AF9 A/J F1 and Mll-AF9 129 F1 having significantly shorter survival, and Mll-AF9 CAST F1 having longer survival, compared to the parental line. Furthermore, we observed a range of hematologic malignancies, with Mll-AF9 A/J F1, Mll-AF9 129 F1 and Mll-AF9 B6 F1 developing exclusively myeloid cell malignancies (myeloproliferative disorder (MPD) and AML) whereas a subset of Mll-AF9 NOD F1 developed MPAL and Mll-AF9 CAST F1 developed ALL. This study provides a novel in vivo experimental model to evaluate the underlying mechanisms by which MLL-AF9 results in diverse leukemia phenotypes and provides definitive experimental evidence that genetic risk factors contribute to survival and phenotype of MLL-rearranged leukemogenesis. ### Competing Interest Statement The authors have declared no competing interest.
151 downloads cancer biology
Sherry Bhalla, David T. Melnekoff, Jonathan Keats, Kenan Onel, Deepu Madduri, Joshua Richter, Shambavi Richard, Ajai Chari, Hearn Jay Cho, Joel T. Dudley, Sundar Jagannath, Alessandro Laganà, Samir Parekh
The remarkable genetic heterogeneity of Multiple Myeloma (MM) poses a significant challenge for proper prognostication and clinical management of patients. Accurate dissection of the genetic and molecular landscape of the disease and the robust identification of homogeneous classes of patients are essential steps to reliable risk stratification and the development of novel precision medicine strategies. Here we introduce MM-PSN, the first multi-omics Patient Similarity Network of newly diagnosed MM. MM-PSN has enabled the identification of three broad patient groups and twelve distinct sub-groups defined by five data types generated from genomic and transcriptomic patient profiling of 655 patients. The MM-PSN classification uncovered novel associations between distinct MM hallmarks with significant prognostic implications and allowed further refinement of risk stratification. Our analysis revealed that gain of 1q is the most important single lesion conferring high risk of relapse, and its association with an MMSET translocation is the most significant determinant of poor outcome. We developed a classifier and validated these results in an independent dataset of 559 pts. Our findings suggest that gain of 1q should be incorporated in routine staging systems and risk assessment tools. The MM-PSN classifier is available as a free resource to allow for an easy implementation in most clinical settings. ### Competing Interest Statement The authors have declared no competing interest.
149 downloads cancer biology
Christopher J. Halbrook, Galloway Thurston, Amy McCarthy, Barbara S. Nelson, Peter Sajjakulnukit, Abigail S Krall, Peter J Mullen, Li Zhang, Sandeep Batra, Andrea Viale, Ben Z. Stanger, Heather R Christofk, Ji Zhang, Marina Pasca di Magliano, Claus Jorgensen, Costas A. Lyssiotis
The pancreatic tumor microenvironment is a complex ecosystem, with numerous cell types functioning to create a niche supporting cancer cell proliferation. Recent efforts are identifying subpopulations among each of these cell types, including diversity among the behavior of cancer cells. In this study, we identify two distinct metabolic subclasses within a single pancreatic tumor cell population capable of metabolic crosstalk. Examining the exchanged metabolites, we find an unexpected role for asparagine in supporting proliferation during mitochondrial inhibition. Furthermore, we find that depletion of extracellular asparagine sensitizes pancreatic tumors to mitochondrial inhibition by phenformin, which could provide a powerful new strategy for this difficult to treat disease. ### Competing Interest Statement CAL is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting GOT1 as a therapeutic approach.
146 downloads cancer biology
Gil Friedman, Oshrat Levi-Galibov, Eyal David, Chamutal Bornstein, Amir Giladi, Maya Dadiani, Avi Mayo, Coral Halperin, Meirav Pevsner-Fischer, Hagar Lavon, Reinat Nevo, Yaniv Stein, H. Raza Ali, Carlos Caldas, Einav Nili-Gal-Yam, Uri Alon, Ido Amit, Ruth Scherz-Shouval
Tumors are supported by cancer-associated fibroblasts (CAFs). CAFs are heterogeneous and carry out distinct cancer-associated functions. Understanding the full repertoire of CAFs and their dynamic changes could improve the precision of cancer treatment. CAFs are usually analyzed at a single time-point using specific markers, and it is therefore unclear whether CAFs display plasticity as tumors evolve. Here, we analyze thousands of CAFs using index and transcriptional single-cell sorting, at several time-points along breast tumor progression in mice, uncovering distinct subpopulations. Strikingly, the transcriptional programs of these subpopulations change over time and in metastases, transitioning from an immune-regulatory program to wound healing and antigen-presentation programs, indicating that CAFs and their functions are dynamic. Two main CAF subpopulations are also found in human breast tumors, where their ratio is associated with disease outcome across subtypes, and is particularly correlated with BRCA mutations in triple-negative breast cancer. These findings indicate that the repertoire of CAFs changes over time in breast cancer progression, with direct clinical implications.
144 downloads cancer biology
Jonathan C. M. Wan, Katrin Heider, Davina Gale, Suzanne Murphy, Eyal Fisher, James Morris, Florent Mouliere, Dineika Chandrananda, Andrea Marshall, Andrew B Gill, Pui Ying Chan, Emily Barker, Gemma Young, Wendy N. Cooper, Irena Hudecova, Francesco Marass, Graham R Bignell, Constantine Alifrangis, Mark R Middleton, Ferdia A Gallagher, Christine Parkinson, Amer Durrani, Ultan McDermott, Christopher G. Smith, Charles Massie, Pippa G Corrie, Nitzan Rosenfeld
Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Patients with small tumors have few copies of ctDNA in plasma, resulting in limited sensitivity to detect low-volume or residual disease. We show that sampling limitations can be overcome and sensitivity for ctDNA detection can be improved by massively parallel sequencing when hundreds to thousands of mutations are identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) analysis pipeline, which combines patient-specific mutation lists with both custom error-suppression methods and signal enrichment based on biological features of ctDNA. In this framework, the sensitivity can be estimated independently for each sample based on the number of informative reads, which is the product of the number of mutations analyzed and the average depth of unique sequencing reads. We applied INVAR to deep sequencing data generated by custom hybrid-capture panels, and showed that when ~106 informative reads were obtained INVAR allowed detection of tumor-derived DNA fractions to parts per million (ppm). In serial samples from patients with advanced melanoma on treatment, we detected ctDNA when imaging confirmed tumor volume of ~1cm3. In patients with resected early-stage melanoma, ctDNA was detected in 40% of patients who later relapsed, with higher rates of detection when more informative reads were obtained. We further demonstrated that INVAR can be generalized and allows improved detection of ctDNA from whole-exome and low-depth whole-genome sequencing data.
143 downloads cancer biology
Microglia are resident myeloid cells in the central nervous system (CNS) that control homeostasis and protect CNS from damage and infections. Microglia and peripheral myeloid cells accumulate and adapt tumor supporting roles in human glioblastomas that show prevalence in men. Cell heterogeneity and functional phenotypes of myeloid subpopulations in gliomas remain elusive. Single-cell RNA sequencing (scRNA-seq) of CD11b+ myeloid cells in naive and GL261 glioma-bearing mice revealed distinct profiles of microglia, infiltrating monocytes/macrophages and CNS border-associated macrophages. We demonstrated an unforeseen molecular heterogeneity among myeloid cells in naive and glioma-bearing brains, validated selected marker proteins and showed distinct spatial distribution of identified subsets in experimental gliomas. We found higher expression of MHCII encoding genes in glioma-activated male microglia, which was corroborated in bulk and scRNA-seq data from human diffuse gliomas. Sex-specific gene expression in glioma-activated microglia may be relevant to sex differences in incidence and outcomes of glioma patients. ### Competing Interest Statement The authors have declared no competing interest.
142 downloads cancer biology
Stefan C. Dentro, Ignaty Leshchiner, Kerstin Haase, Maxime Tarabichi, Jeff Wintersinger, Amit G. Deshwar, Kaixian Yu, Yulia Rubanova, Geoff Macintyre, Jonas Demeulemeester, Ignacio Vázquez-García, Kortine Kleinheinz, Dimitri G. Livitz, Salem Malikic, Nilgun Donmez, Subhajit Sengupta, Pavana Anur, Clemency Jolly, Marek Cmero, Daniel Rosebrock, Steven Schumacher, Yu Fan, Matthew Fittall, Ruben M. Drews, Xiaotong Yao, Juhee Lee, Matthias Schlesner, Hongtu Zhu, David J. Adams, Gad Getz, Paul C. Boutros, Marcin Imielinski, Rameen Beroukhim, S. Cenk Sahinalp, Yuan Ji, Martin Peifer, Iñigo Martincorena, Florian Markowetz, Ville Mustonen, Ke Yuan, Moritz Gerstung, Paul T. Spellman, Wenyi Wang, Quaid D. Morris, David C. Wedge, Peter Van Loo, on behalf of the PCAWG Evolution and Heterogeneity Working Groupthe PCAWG consortium., the PCAWG consortium
Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin and drivers of ITH across cancer types are poorly understood. To address this question, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples, spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions, with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types, and identify cancer type specific subclonal patterns of driver gene mutations, fusions, structural variants and copy-number alterations, as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution, and provide an unprecedented pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data. ### Competing Interest Statement R.B. owns equity in Ampressa Therapeutics. G.G. receives research funds from IBM and Pharmacyclics and is an inventor on patent applications related to MuTect, ABSOLUTE, MutSig, MSMuTect and POLYSOLVER. I.L. is a consultant for PACT Pharma. B.J.R. is a consultant at and has ownership interest (including stock and patents) in Medley Genomics. All other authors declare no competing interests.
142 downloads cancer biology
A major challenge of targeting metabolism for cancer therapy is pathway redundancy, where multiple sources of critical nutrients can limit the effectiveness of some metabolism-targeted therapies. Here, we analyzed lineage-dependent gene expression in human breast tumors to identify differences in metabolic gene expression that may limit pathway redundancy and create therapeutic vulnerabilities. We found that the serine synthesis pathway gene PSAT1 is the most depleted metabolic gene in luminal breast tumors relative to basal tumors. Low PSAT1 prevents de novo serine biosynthesis and sensitizes luminal breast cancer cells to serine and glycine starvation in vitro and in vivo. This PSAT1 expression disparity, which pre-exists in the putative cells-of-origin of basal and luminal tumors, is due to luminal-specific hypermethylation of the PSAT1 gene. Together, our data demonstrates that luminal breast tumors are auxotrophic for serine and are uniquely sensitive to dietary serine starvation. ### Competing Interest Statement The authors have declared no competing interest.
140 downloads cancer biology
Jarrett R Remsberg, Radu M. Suciu, Noemi A Zambetti, Thomas W Hanigan, Ari J. Firestone, Anagha Inguva, Amy Long, Nhi Ngo, Kenneth M. Lum, Cassandra L Henry, Stewart K Richardson, Marina Predovic, Ben Huang, Amy R Howell, Micah J. Niphakis, Kevin Shannon, Benjamin F Cravatt
A subset of Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared to Palmostatin M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MEK inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes in modulating the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers. ### Competing Interest Statement The authors have declared no competing interest.
139 downloads cancer biology
Adele M. Musicant, Kshitij Parag-Sharma, Weida Gong, Monideepa Sengupta, Arindam Chatterjee, Erin C Henry, Yi-Hsuan Tsai, Michele C. Hayward, Siddharth Sheth, Renee Betancourt, Trevor G. Hackman, Ricardo J Padilla, Joel S. Parker, Jimena Giudice, Colin A. Flaveny, David N Hayes, Antonio L. Amelio
Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by the transcriptional co-activator fusion CRTC1-MAML2. The mechanisms by which the chimeric CRTC1-MAML2 oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that CRTC1-MAML2 induces transcriptional activation of the non-canonical PGC-1 α splice variant PGC-1 α 4, which regulates PPAR γ-dependent IGF-1 expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. CRTC1-MAML2 positive tumors are dominated by IGF-1 pathway activation and small molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1R inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPAR γ inhibition with inverse agonists. These results yield insights into the aberrant co-regulatory functions of CRTC1-MAML2 and identify a specific vulnerability that can be exploited for precision therapy. ### Competing Interest Statement The authors have declared no competing interest.
137 downloads cancer biology
Neuroblastoma (NB), derived from the neural crest (NC), is the most common pediatric extracranial solid tumor. Here we establish a platform that allows studying human NBs in mouse-human NC chimeras. Chimeric mice were produced by injecting human NC cells carrying NB relevant oncogenes in-utero into gastrulating mouse embryos. The mice developed tumors composed of a heterogenous cell population that closely resembled that seen in primary NBs of patients but were significantly different from homogenous tumors formed in xenotransplantation models. The human tumors emerged in immunocompetent hosts and were extensively infiltrated by mouse cytotoxic T cells reflecting a vigorous host anti-tumor immune response. However, the tumors blunted the immune response by inducing infiltration of regulatory T cells and expression of immune checkpoints similar to escape mechanisms seen in human cancer patients. Thus, this experimental platform allows studying human tumor initiation, progression, manifestation and tumor - immune-system interactions in an animal model system.
136 downloads cancer biology
Sohrab Salehi, Farhia Kabeer, Nicholas Ceglia, Mirela Andronescu, Marc Williams, Kieran R Campbell, Tehmina Masud, Beixi Wang, Justina Biele, Jazmine Brimhall, Jerome Ting, Allen W. Zhang, Ciara O’Flanagan, Fatemeh Dorri, Nicole Rusk, Hak Woo Lee, Teresa Ruiz de Algara, So Ra Lee, Brian Yu Chieh Cheng, Peter Eirew, Takako Kono, Jennifer Pham, Diljot Grewal, Daniel Lai, Richard Moore, Andrew J. Mungall, Marco A. Marra, IMAXT Consortium, Andrew McPherson, Alexandre Bouchard-Côté, Samuel Aparicio, Sohrab P. Shah
Tumour fitness landscapes underpin selection in cancer, impacting etiology, evolution and response to treatment. Progress in defining fitness landscapes has been impeded by a lack of timeseries perturbation experiments over realistic intervals at single cell resolution. We studied the nature of clonal dynamics induced by genetic and pharmacologic perturbation with a quantitative fitness model developed to ascribe quantitative selective coefficients to individual cancer clones, enable prediction of clone-specific growth potential, and forecast competitive clonal dynamics over time. We applied the model to serial single cell genome (>60,000 cells) and transcriptome (>58,000 cells) experiments ranging from 10 months to 2.5 years in duration. We found that genetic perturbation of TP53 in epithelial cell lines induces multiple forms of copy number alteration that confer increased fitness to clonal populations with measurable consequences on gene expression. In patient derived xenografts, predicted selective coefficients accurately forecasted clonal competition dynamics, that were validated with timeseries sampling of experimentally engineered mixtures of low and high fitness clones. In cisplatin-treated patient derived xenografts, the fitness landscape was inverted in a time-dependent manner, whereby a drug resistant clone emerged from a phylogenetic lineage of low fitness clones, and high fitness clones were eradicated. Moreover, clonal selection mediated reversible drug response early in the selection process, whereas late dynamics in genomically fixed clones were associated with transcriptional plasticity on a fixed clonal genotype. Together, our findings outline causal mechanisms with implication for interpreting how mutations and multi-faceted drug resistance mechanisms shape the etiology and cellular fitness of human cancers. ### Competing Interest Statement SPS and SA are shareholders and consultants of Contextual Genomics Inc.
136 downloads cancer biology
Aishwarya Subramanian, Mathew Hall, Huayun Hou, Marat Mufteev, Bin Yu, Kyoko E Yuki, Haruka Nishimura, Anson Sathaseevan, Benjamin Lant, Beibei Zhai, James Ellis, Michael D. Wilson, Mads Daugaard, W. Brent Derry
Alternative polyadenylation of pre-mRNA has been recently shown to play important roles in development and cancer. Activating mutations in the Ras oncogene are common drivers of many human cancers but the mechanisms by which they cooperate with alternative polyadenylation are not known. By exploiting the genetics of C. elegans, we identified cfim-1/CFIm25, a subunit of the alternative polyadenylation machine, as a key determinant of hyperactive Ras function. Ablation of cfim-1 increased penetrance of multivulva phenotype in let-60/Ras gain-of-function (gf) mutant through shortening of transcripts at the 3′ untranslated region, including p21 activated kinase pak-1/PAK1 and multidrug transporter mrp-5/ABCC1. Depletion of CFIm25 in human KRAS-driven cancer cells resulted in a similar shortening of 3′ untranslated regions in the PAK1 and ABCC1 transcripts, which caused an epithelial-to mesenchymal transition and increased cell migration. Exploiting the mechanisms by which alternative polyadenylation affects activated oncogene output could offer novel approaches for the treatment of Ras-driven tumors. ### Competing Interest Statement The authors have declared no competing interest.
135 downloads cancer biology
To understand the architecture of a tissue it is necessary to know both the cell populations and their physical relationships to one another. Single-cell RNA-Seq (scRNA-Seq) has made significant progress towards the unbiased and systematic characterization of the cell populations within a tissue, as well as their cellular states, by studying hundreds and thousands of cells in a single experiment. However, the characterization of the spatial organization of individual cells within a tissue has been more elusive. The recently introduced "spatial transcriptomics" method (ST) reveals the spatial pattern of gene expression within a tissue section at a resolution of one thousand 100 µm spots, each capturing the transcriptomes of ~10-20 cells. Here, we present an approach for the integration of scRNA-Seq and ST data generated from the same sample of pancreatic cancer tissue. Using markers for cell-types identified by scRNA-Seq, we robustly deconvolved the cell-type composition of each ST spot, to generate a spatial atlas of cell proportions across the tissue. Studying this atlas, we found that distinct spatial localizations accompany each of the three cancer cell populations that we identified. Strikingly, we find that subpopulations defined in the scRNA-Seq data also exhibit spatial segregation in the atlas, suggesting such an atlas may be used to study the functional attributes of subpopulations. Our results provide a framework for creating a tumor atlas by mapping single-cell populations to their spatial region, as well as the inference of cell architecture in any tissue.
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