Mouse models reveal core principles of tissue-specific cancer evolution
Oncogenes like KRAS display striking tissue-specificity in their oncogenic potential, genetic interactions and phenotypic effects, but the underlying determinants remain largely unresolved. To address these fundamental questions, we developed the Mouse Cancer Cell Line Atlas, a broad utility resource of 590 comprehensively characterized models across a wide range of entities (www.mcca.tum.de). Comparative and functional studies using this resource, human cohorts and mouse models uncovered general principles of KRAS-driven cancer evolution, governed by mechanisms shaping tissue-specificity at different levels: First, we show that dosage gain of mutant KRAS via allelic imbalance exerts cell type-specific effects, such as developmental reprogramming in the pancreas. Differential selection of such dosage-sensitive processes defines the timing and phenotypic outcomes of KRAS imbalance across entities. Second, we highlight how tissue- and stage-specific evolutionary requirements, such as block of differentiation in the intestine, select for KRAS-collaborating alterations. Third, we uncovered tissue-specific epistatic interactions between KRAS imbalance and tumor suppression, as shown for CDKN2A, which displays cell type-dependent chromatin repression. We demonstrate that resulting reciprocal dosage-sensitivities dictate the entity-specific patterns of tumor-suppressor alterations in human cancers, explaining their frequency, extent/zygosity and acquisition chronology. These paradigmatic findings thus highlight how the interplay of intrinsic and acquired determinants instructs cancer evolution along deterministic trajectories in different tissues – with predictable molecular patterns, temporal dynamics and phenotypic outcomes. Our study provides major advances towards a mechanistic understanding of cancer genomes.<br /> <br /> !Please note: All data is currently being uploaded!<br /> <br /> Sub-studies:<br /> *PRJEB105229: Bulk 3' transcript end RNA sequencing of mouse cancer cell lines from the Mouse Cancer Cell line Atlas (MCCA), spanning 22 lineages and 46 cancer types.<br /> *PRJEB105230: Low-coverage whole genome sequencing of mouse cancer cell lines from the Mouse Cancer Cell line Atlas (MCCA).<br /> *PRJEB105231: Whole exome sequencing of mouse cancer cell lines from the Mouse Cancer Cell line Atlas (MCCA).<br /> *PRJEB105330: Bulk 3' transcript end RNA sequencing of doxycycline-inducible KRAS(G12D) expression in non-transformed human pancreatic, lung and colon cell lines and a mouse small intestinal epithelial cell line.<br /> *PRJEB105331: Bulk 3' transcript end RNA sequencing of mouse intestinal tissues across defined stages of Kras(G12D)-driven serrated intestinal tumor progression.<br /> *PRJEB105332: Bulk 3' transcript end RNA sequencing of MCCA hepatic cancer cell lines under 2D versus 3D culture conditions.<br /> *PRJEB105333: Bulk 3' transcript end RNA sequencing of acinar-to-ductal transdifferentiation in mouse pancreatic cells.