Abstract 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 such fundamental questions, we developed the Mouse Cancer Cell line Atlas (MCCA), a broad utility resource encompassing 590 comprehensively characterized models from a wide spectrum of entities. Comparative and functional studies using the MCCA resource, human cohorts and mouse models uncovered general principles guiding KRAS-initiated cancer evolution. We describe how tissue context affects diverse aspects of evolution, including the role of mutant KRAS gene dosage variation, the relevance of collaborating cancer pathways, or the sequential order of genetic alterations. Mechanisms governing tissue-specific evolution transpired at different levels: First, we show that mutant KRAS dosage increase through allelic imbalance exerts cell type-specific effects, such as reactivation of developmental programs in the pancreas. Selection of such dosage-sensitive processes defines the timing of KRAS imbalance and its phenotypic outcomes in individual 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 demonstrated for CDKN2A, which displays distinct levels of chromatin repression in different cell types. We show 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 findings thus highlight how the interplay of pre-existing and acquired determinants instructs cancer evolution along deterministic trajectories in different tissues - with predictable quantitative molecular patterns, temporal dynamics and phenotypic outcomes. Our study provides major advances towards a mechanistic understanding of cancer genomes. Citation Format: Sebastian Mueller, Niklas de Andrade Krätzig, Markus Tschurtschenthaler, Miguel G. Silva, Chiara Thordsen, Riccardo Trozzo, Perrine Simon, Frederic Saab, Thorsten Kaltenbacher, Magdalena Zukowska, Daniele Lucarelli, Rupert Öllinger, Joscha Griger, Nina Groß, Tanja Groll, Linus R. Schömig, Stefanie Baerthel, Chiara Falcomatà, Alexander Strong, Cordelia Brandt, Mulham Najajreh, Aristeidis Papargyriou, Roman Maresch, Ute Jungwirth, Maximilian Reichert, George S. Vassiliou, Daniel F. Alonso, Pier-Luigi Lollini, Jean J. Zhao, Louis Chesler, Clare M. Isacke, Angela Riedel, Marc Schmidt-Supprian, Günter Schneider, Trevor D. Lawley, Gordon Dougan, Katja Steiger, Nathalie Conte, Allan Bradley, Lena Rad, Dieter Saur, Roland Rad. The mouse cancer cell line atlas reveals core principles of tissue-specific cancer evolution abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6794.
Mueller et al. (Fri,) studied this question.