A disease model resource reveals core principles of tissue-specific cancer evolution
Article Date: 25 February 2026
Article URL: https://www.nature.com/articles/s41586-026-10187-2
Article Image: https://media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41586-026-10187-2/MediaObjects/41586_2026_10187_Fig1_HTML.png
Summary
This paper describes the Mouse Cancer Cell line Atlas (MCCA), a curated resource of 590 mouse cancer cell lines across 46 disease types with multilayered genomic, transcriptomic, phenotypic and clinical annotation available at www.mcca.tum.de. The authors provide computational tools to infer strain background and MHC haplotypes from sequence data, enabling immunophenotyping and rational selection of immunocompetent transplant recipients. Using MCCA plus functional and human data they dissect KRAS-driven oncogenesis across pancreas, lung and intestine, revealing tissue-specific principles: KRAS mutant increased gene dosage (iGD) is positively selected and linked to worse outcomes, but its timing, cellular effects and interactions with tumour suppressors (notably CDKN2A) differ by tissue. Epigenetic regulation (Polycomb/H3K27me3) of CDKN2A helps explain these differences and why the order and selective pressure for CDKN2A loss varies between organs.
Key Points
- MCCA: 590 mouse cancer cell lines (22 lineages, 46 disease types) with harmonised molecular, phenotypic and clinical metadata, accessible via a cBioPortal instance (www.mcca.tum.de).
- New computational immunophenotyping methods infer strain composition and MHC haplotypes from sequencing (StrainMapper-like approach), guiding transplant recipient choice and predicting an “effective” protein-altering TMB that includes immunogenic germline strain SNPs.
- KRAS mutant increased gene dosage (iGD) is common across mouse and human cancers and correlates with poorer survival; decreased dosage (dGD) is rare—iGD is under positive selection.
- Tissue-specific timing: KRAS iGD arises early in pancreatic tumour evolution (driving de-differentiation), later in lung carcinomas, and at carcinoma stage in intestinal serrated tumours (after WNT-driven block of differentiation).
- KRAS dosage effects are context dependent: in pancreas/lung high KRAS doses drive de-differentiation and invasion programmes, whereas in intestine they primarily drive proliferation.
- CDKN2A shows tissue-specific chromatin states (active in pancreas, Polycomb-repressed in intestine, bivalent in lung) that determine its responsiveness to KRAS signalling and the selective pressure to inactivate CDKN2A.
- Order of alterations differs by tissue: in pancreas CDKN2A loss often precedes and licences KRAS iGD; in lung and intestine KRAS iGD can occur before CDKN2A homozygous loss, which may be acquired later to enhance aggressiveness.
- MCCA resource supports immunocompetent transplantation experiments, functional screens and cross-species comparisons to model human disease phenotypes and test (immuno)therapies.
Content summary
The authors assembled and rigorously characterised a comprehensive mouse cell line collection (MCCA) and made all data available via a mouse-adapted cBioPortal. They developed pipelines optimised for mouse genomes (MoCaSeq) and strain/MHC signature SNP panels to infer genetic background and MHC haplotypes from sequencing data. This enables prediction of recipient compatibility and calculation of an “effective” protein-altering tumour mutational burden that accounts for immunogenic strain-specific germline variants in transplant scenarios.
They used MCCA plus human datasets and experimental models to study KRAS-driven cancers. Integrative analyses show KRAS mutant increased dosage (iGD) is frequently selected and associated with worse survival. However, the stage at which iGD appears and its biological impact vary by tissue: in the pancreas iGD appears early and promotes de-differentiation (with strong CDKN2A-mediated senescence as a barrier), in the lung iGD is linked to progression to carcinoma, and in the intestine iGD only expands clonally after WNT pathway-driven block of differentiation (adenoma stage).
Mechanistically, tissue-specific chromatin regulation of CDKN2A (active in pancreas, Polycomb-repressed in intestine) shapes how KRAS engages tumour suppression, explaining differential selective pressure to lose CDKN2A and the observed order of events. Functional experiments (organoids, inducible KRAS expression, transposon screens, in vivo transplantations and CRISPR somatic mutagenesis) support these conclusions and demonstrate the value of the MCCA for mechanistic and preclinical studies.
Context and relevance
This work provides a major new mouse model resource that complements human cell line collections by enabling controlled modelling of genetic contexts, sampling of defined disease stages and immunocompetent transplants. The study clarifies why the same oncogene (KRAS) produces distinct evolutionary routes across tissues — a key question for precision prevention and therapy. The tissue-specific link between KRAS dosage, CDKN2A chromatin state and timing of mutations helps explain clinical patterns (variation in CDKN2A loss, KRAS amplifications and therapy responses) and suggests context-aware therapeutic strategies.
Why should I read this
Short version: if you care about how cancers evolve differently by tissue, this paper is gold. It bundles a huge, well-annotated mouse cell line resource with tools to pick the right immunocompetent model, then uses it to show why KRAS behaves differently in pancreas, lung and intestine — all tied to epigenetic control of a key tumour suppressor. Saves you weeks of digging through disparate mouse studies.