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

Oncogenes such as KRAS display marked tissue specificity in their oncogenic potential, genetic interactions and phenotypic effects, but the underlying determinants remain largely unresolved<sup>1-5</sup>. 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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Publication Details

Journal
Nature
Published
2026-02-25
DOI
https://doi.org/10.1038/s41586-026-10187-2
Primary Topic
Cancer Cells and Metastasis
Type
article
Field-Weighted Citation Impact
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article

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

Magdalena Żukowska, Nathalie A. Conte, Markus Tschurtschenthaler, Daniele Lucarelli et al.
Nature
Cancer Cells and Metastasis
article

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

Magdalena Żukowska, Nathalie A. Conte, Markus Tschurtschenthaler, Daniele Lucarelli, Niklas de Andrade Krätzig, Riccardo Trozzo, Stefanie Bärthel, Aristeidis Papargyriou, Christine Klement, Juán José Montero, Roman Maresch, Angela Riedel, Christian Schneeweis, Thorsten Kaltenbacher, Filippo Beleggia, Michael Quante, Katharina A. N. Collins, Rupert Öllinger, Jeroen M. Bugter, Pier‐Luigi Lollini, Joscha Griger, Linus Schömig, Martin L. Sos, Antonio Enrico Zaurito, Ignacio Varela, Markus Moser, Juan Enrique Cadiñanos, Maximilian Reichert, Chiara Falcomatà, Sebastian Bürger, Marc Schmidt-Supprian, Alexander Belka, J. Löprich, Kaede V. Sullivan, Tanja Groll, Rad Roland, Jens Neumann, Mónica Musteanu, Alexander Strong, Simon Clare, Sebastian Mueller, Jean J. Zhao, Lena Rad, Mulham Najajreh, Louis Chesler, Cordelia Brandt, Carsten Marr, David Sailer, Katja Steiger, Miguel G. Silva, Dieter Saur, Christian J. Braun, Günter Schneider, Nina Groß, Clare M. Isacke, Daniel F. Alonso, George Vassiliou, Frederic Saab, Hans C. Reinhardt, Chiara Thordsen, Lisa M. Fröhlich, Perrine SIMON, Ute Jungwirth, Gordon Dougan, Mariano Barbacid
article en

Abstract

Oncogenes such as KRAS display marked tissue specificity in their oncogenic potential, genetic interactions and phenotypic effects, but the underlying determinants remain largely unresolved<sup>1-5</sup>. 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.

Nature
Broad Institute (US), Universidad Complutense de Madrid (ES), Universidad de Cantabria (ES), Royal Marsden NHS Foundation Trust (GB), Harvard University (US), National University of Quilmes (AR), Institute of Cancer Research (GB), German Cancer Research Center (DE), University of Cologne (DE), Center for Integrated Protein Science Munich (DE), Heidelberg University (DE), Breast Cancer Now (GB), Gobierno del Principado de Asturias (ES), University Medical Center Freiburg (DE), Instituto de Salud Carlos III (ES), Cambridge University Hospitals NHS Foundation Trust (GB), Wellcome Sanger Institute (GB), Helmholtz Zentrum München (DE), LMU Klinikum (DE), Centro Científico Tecnológico - San Juan (AR), Instituto de Biomedicina y Biotecnología de Cantabria (ES), Centro Nacional de Epidemiología (ES), Translational Research in Oncology (FR), Molecular Microbiology and Genomics Consultants (Germany) (DE), Universitätsmedizin Göttingen (DE), Hopp Children's Cancer Center Heidelberg (DE), Dana-Farber Cancer Institute (US), Azienda USL di Bologna (IT), Essen University Hospital (DE), München Klinik (DE), Institute of Clinical Cancer Research (DE), Universitätsklinikum Würzburg (DE), Max Planck Institute of Psychiatry (DE), University Hospital Cologne (DE), Center for Systems Biology (US), Centro de Investigación Biomédica en Red de Cáncer (ES), Deutsches Konsortium für Translationale Krebsforschung (DE), Technical University of Munich (DE), University of Göttingen (DE), University of Newcastle Australia (AU), Ludwig-Maximilians-Universität München (DE), Newcastle University (GB), University of Bologna (IT)
Openalex Percentile: Top 42%
Cancer Cells and Metastasis
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