A disease model resource reveals core principles of tissue-specific cancer evolution
Abstract
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 1–5 . 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.
Article Details
Authors (66)
Sebastian Mueller
Niklas de Andrade Krätzig
Markus Tschurtschenthaler
Miguel G. Silva
Chiara Thordsen
Riccardo Trozzo
Perrine Simon
Frederic Saab
Thorsten Kaltenbacher
Magdalena Zukowska
Daniele Lucarelli
Rupert Öllinger
Joscha Griger
Nina Groß
Tanja Groll
Jessica Löprich
Antonio E. Zaurito
Linus R. Schömig
Jeroen M. Bugter
Stefanie Bärthel
Chiara Falcomatà
Alexander Strong
Cordelia Brandt
Mulham Najajreh
Aristeidis Papargyriou
Roman Maresch
Katharina A. N. Collins
David Sailer
Christian Schneeweis
Sebastian Burger
Lisa M. Fröhlich
Christine Klement
Alexander Belka
Juan J. Montero
Ute Jungwirth
Maximilian Reichert
Markus Moser
Jens Neumann
George Vassiliou
Juan Cadiñanos
Ignacio Varela
Carsten Marr
Daniel F. Alonso
Pier-Luigi Lollini
Jean Zhao
Louis Chesler
Clare M. Isacke
Angela Riedel
Christian J. Braun
Martin L. Sos
Filippo Beleggia
Hans C. Reinhardt
Monica Musteanu
Mariano Barbacid
Michael Quante
Marc Schmidt-Supprian
Günter Schneider
Simon Clare
Trevor D. Lawley
Gordon Dougan
Katja Steiger
Nathalie Conte
Allan Bradley
Lena Rad
Dieter Saur
Roland Rad