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Mueller, S.* ; de Andrade Krätzig, N.* ; Tschurtschenthaler, M.* ; Silva, M.G.* ; Thordsen, C.* ; Trozzo, R.* ; Simon, P.* ; Saab, F.* ; Kaltenbacher, T.* ; Zukowska, M.* ; Lucarelli, D. ; Öllinger, R.* ; Griger, J.* ; Groß, N.* ; Groll, T.* ; Löprich, J.* ; Zaurito, A.E.* ; Schömig, L.R.* ; Bugter, J.M.* ; Bärthel, S.* ; Falcomatà, C.* ; Strong, A.* ; Brandt, C.* ; Najajreh, M.* ; Papargyriou, A. ; Maresch, R.* ; Collins, K.A.N.* ; Sailer, D.* ; Schneeweis, C.* ; Burger, S.* ; Fröhlich, L.M.* ; Klement, C.* ; Belka, A.* ; Montero, J.J.* ; Jungwirth, U.* ; Reichert, M.* ; Moser, M.* ; Neumann, J.* ; Vassiliou, G.* ; Cadiñanos, J.* ; Varela, I.* ; Marr, C. ; Alonso, D.F.* ; Lollini, P.L.* ; Zhao, J.* ; Chesler, L.* ; Isacke, C.M.* ; Riedel, A.* ; Braun, C.J.* ; Sos, M.L.* ; Beleggia, F.* ; Reinhardt, H.C.* ; Musteanu, M.* ; Barbacid, M.* ; Quante, M.* ; Schmidt-Supprian, M.* ; Schneider, G.* ; Clare, S.* ; Lawley, T.D.* ; Dougan, G.* ; Steiger, K.* ; Conte, N.* ; Bradley, A.* ; Rad, L.* ; Saur, D.* ; Rad, R.*

A disease model resource reveals core principles of tissue-specific cancer evolution.

Nature, DOI: 10.1038/s41586-026-10187-2 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Oncogenes such as KRAS display marked tissue specificity in their oncogenic potential, genetic interactions and phenotypic effects, but the underlying determinants remain largely unresolved1-5. Here, to address these 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 platform, human cohorts and mice identified core principles underlying tissue-specific evolution of KRAS-initiated cancers. First, we show that mutant KRAS dosage gain through allelic imbalance exerts cell-type-specific effects, defining its timing across entities, as exemplified by dosage-sensitive developmental reprogramming during pancreatic cancer initiation. 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 identified context-dependent epistatic KRAS-tumour suppressor interactions and show that reciprocal dosage sensitivities dictate the entity-specific patterns of cancer gene alterations, explaining their frequency, zygosity and acquisition chronology. These findings highlight how intrinsic and acquired determinants instruct cancer evolution in different tissues, with predictable molecular patterns, temporal dynamics and phenotypic outcomes. Our study provides major advances towards a mechanistic understanding of cancer genomes.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Epistasis ; Cancer ; Disease ; Phenotype ; Reprogramming ; Evolutionary Dynamics ; Mechanism (biology) ; Epigenetics ; Genome; Epithelial-cells; Tumor Suppression; Gene Discovery; Mouse Models; Expression; Lung; Genome; Immortalization; Locus; Instability
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)
Institute of Stem Cell Research (ISF)
Institute of AI for Health (AIH)
Förderungen Technische Universität München