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Lookup NU author(s): Dr Ute JungwirthORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Mueller S, de Andrade Krätzig N, Tschurtschenthaler M, Silva M, Thordsen C, Trozzo R, Simon P, Saab F, Kaltenbacher T, Zukowska M, Lucarelli D, Öllinger R, Griger J, Grosz N, Groll T, Löprich J, Zaurito A, Schömig L, Bugter J, Bärthel S, Falcomatà C, Strong A, Brandt C, Najajreh M, Papargyriou A, Maresch R, Collins K, Sailer D, Schneeweis C, Burger S, Fröhlich L, Klement C, Belka A, Montero J, Jungwirth U, Reichert M, Moser M, Neumann J, Vassiliou G, Cadiñanos J, Varela I, Marr C, Alonso D, Lollini P, Zhao J, Chesler L, Isacke C, Riedel A, Braun C, Sos M, Beleggia F, Reinhardt H, Musteanu M, Barbacid M, Quante M, Schmidt-Supprian M, Schneider G, Clare S, Lawley T, Dougan G, Steiger K, Conte N, Bradley A, Rad L, Saur D, Rad R
Publication type: Article
Publication status: Published
Journal: Nature
Year: 2026
Volume: 653
Issue: 8113
Pages: 265-276
Print publication date: 07/05/2026
Online publication date: 25/02/2026
Acceptance date: 23/01/2026
Date deposited: 21/07/2026
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41586-026-10187-2
DOI: 10.1038/s41586-026-10187-2
Data Access Statement: The following reference genomes were used: GRCm38.p6 (https://www.ncbi.nlm.nih.gov/datasets/genome/GCF_000001635.26/) and GRCh38.p12 (https://www.ncbi.nlm.nih.gov/datasets/genome/GCF_000001405.38/). The following gene annotations were used: mouse gene annotations (GENCODE mouse M25; https://www.gencodegenes.org/mouse/release_M25.html), human gene annotations (GENCODE human v38; https://www.gencodegenes.org/human/release_38.html), Agilent WES mouse target regions (Agilent SureSelect XT Mouse All Exon, V1; https://earray.chem.agilent.com/suredesign/), Agilent WES human target regions (Agilent SureSelect Human All Exon V7 exon, S31285117; https://earray.chem.agilent.com/suredesign/) and Ensembl human-mouse orthologous gene names (v103; https://doi.org/10.1093/nar/gkae1071). Continues at https://www.nature.com/articles/s41586-026-10187-2#data-availability and https://www.nature.com/articles/s41586-026-10187-2#code-availability
PubMed id: 41741657
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