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rss-bridge 2026-03-01T04:04:53.085637855+00:00

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

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  • Article

Open access

  • Published: 25 February 2026

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

  • Sebastian Mueller

orcid.org/0009-0008-1514-30271,2 na1,

  • Niklas de Andrade Krätzig

orcid.org/0000-0003-2141-67451,2 na1,

  • Markus Tschurtschenthaler

orcid.org/0000-0002-0060-47902,3,4,5 na1,

  • Miguel G. Silva1,2,
  • Chiara Thordsen1,2,
  • Riccardo Trozzo

orcid.org/0000-0002-5889-994X1,2,

  • Perrine Simon1,2,
  • Frederic Saab

orcid.org/0000-0002-3351-82742,3,4,

  • Thorsten Kaltenbacher

orcid.org/0000-0001-8233-47491,2,

  • Magdalena Zukowska2,3,4,
  • Daniele Lucarelli

orcid.org/0000-0002-0393-38482,3,4,6,

  • Rupert Öllinger

orcid.org/0000-0002-2292-59821,2,

  • Joscha Griger

orcid.org/0000-0001-8666-33711,2,

  • Nina Groß1,2,
  • Tanja Groll

orcid.org/0000-0002-9049-91457,8,

  • Jessica Löprich1,2,
  • Antonio E. Zaurito2,3,4,
  • Linus R. Schömig

orcid.org/0000-0002-9434-03349,

  • Jeroen M. Bugter

orcid.org/0000-0001-9920-29371,2,

  • Stefanie Bärthel

orcid.org/0000-0001-5986-48642,3,4,

  • Chiara Falcomatà

orcid.org/0000-0001-9269-25822,3,4,

  • Alexander Strong10,
  • Cordelia Brandt10,
  • Mulham Najajreh

orcid.org/0000-0002-3355-886611,12,13,14,

  • Aristeidis Papargyriou

orcid.org/0000-0002-2577-473711,12,13,14,15,

  • Roman Maresch

orcid.org/0000-0003-3393-88821,2,

  • Katharina A. N. Collins1,2,
  • David Sailer1,2,
  • Christian Schneeweis2,3,4,
  • Sebastian Burger

orcid.org/0009-0005-1326-56861,2,

  • Lisa M. Fröhlich5,16,17,
  • Christine Klement

orcid.org/0000-0003-1446-37031,2,

  • Alexander Belka1,2,
  • Juan J. Montero1,2,
  • Ute Jungwirth

orcid.org/0000-0002-4673-309618,

  • Maximilian Reichert5,11,12,13,14,
  • Markus Moser

orcid.org/0000-0001-8825-556619,

  • Jens Neumann20,
  • George Vassiliou

orcid.org/0000-0003-4337-802221,

  • Juan Cadiñanos

orcid.org/0000-0001-7561-775922,

  • Ignacio Varela

orcid.org/0000-0002-0969-506X23,

  • Carsten Marr

orcid.org/0000-0003-2154-45525,24,

  • Daniel F. Alonso

orcid.org/0000-0002-0601-613X25,26,

  • Pier-Luigi Lollini27,28,
  • Jean Zhao

orcid.org/0000-0002-4561-568829,30,31,32,

  • Louis Chesler

orcid.org/0000-0001-7842-206833,

  • Clare M. Isacke

orcid.org/0000-0002-9222-334534,

  • Angela Riedel35,
  • Christian J. Braun1,36,37,
  • Martin L. Sos5,16,17,38,
  • Filippo Beleggia

orcid.org/0000-0003-0234-709438,39,40,

  • Hans C. Reinhardt

orcid.org/0000-0001-5706-93495,41,

  • Monica Musteanu42,43,
  • Mariano Barbacid42,44,
  • Michael Quante5,9,
  • Marc Schmidt-Supprian

orcid.org/0000-0002-8543-61662,5,19,

  • Günter Schneider

orcid.org/0000-0003-1840-45082,45,46,

  • Simon Clare10,
  • Trevor D. Lawley

orcid.org/0000-0002-4805-621X10,

  • Gordon Dougan10,47,
  • Katja Steiger

orcid.org/0000-0002-7269-54335,7,8,

  • Nathalie Conte10,
  • Allan Bradley10,
  • Lena Rad2,4,5,
  • Dieter Saur

orcid.org/0000-0001-5874-02102,3,4,5,13 na2 &

  • …
  • Roland Rad

orcid.org/0000-0002-6849-96591,2,5 na2

Nature

(2026)Cite this article

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Subjects

  • Cancer genetics
  • Cancer models
  • Oncogenes

Abstract

Oncogenes such as KRAS display marked tissue specificity in their oncogenic potential, genetic interactions and phenotypic effects, but the underlying determinants remain largely unresolved1,2,3,4,5. 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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