Non-canonical functions of SNAIL drive context-specific cancer progression

Mariel C. Paul, Christian Schneeweis, Chiara Falcomatà, Chuan Shan, Daniel Rossmeisl, Stella Koutsouli, Christine Klement, Magdalena Zukowska, Sebastian A. Widholz, Moritz Jesinghaus, Konstanze K. Heuermann, Thomas Engleitner, Barbara Seidler, Katia Sleiman, Katja Steiger, Markus Tschurtschenthaler, Benjamin Walter, Sören A. Weidemann, Regina Pietsch, Angelika Schnieke, Roland M. Schmid, Maria S. Robles, Geoffroy Andrieux, Melanie Boerries, Roland Rad, Günter Schneider and Dieter Saur ()
Additional contact information
Mariel C. Paul: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Christian Schneeweis: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Chiara Falcomatà: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Chuan Shan: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Daniel Rossmeisl: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Stella Koutsouli: Faculty of Medicine, LMU Munich
Christine Klement: Technical University of Munich
Magdalena Zukowska: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Sebastian A. Widholz: Technical University of Munich
Moritz Jesinghaus: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Konstanze K. Heuermann: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Thomas Engleitner: Technical University of Munich
Barbara Seidler: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Katia Sleiman: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Katja Steiger: Technische Universität München
Markus Tschurtschenthaler: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Benjamin Walter: Technische Universität München
Sören A. Weidemann: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Regina Pietsch: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Angelika Schnieke: Technische Universität München
Roland M. Schmid: Technische Universität München
Maria S. Robles: Faculty of Medicine, LMU Munich
Geoffroy Andrieux: University of Freiburg
Melanie Boerries: University of Freiburg
Roland Rad: Technical University of Munich
Günter Schneider: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Dieter Saur: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent oncogenic SNAIL functions in cancer. Using genetic models, we systematically interrogated SNAIL effects in various oncogenic backgrounds and tissue types. SNAIL-related phenotypes displayed remarkable tissue- and genetic context-dependencies, ranging from protective effects as observed in KRAS- or WNT-driven intestinal cancers, to dramatic acceleration of tumorigenesis, as shown in KRAS-induced pancreatic cancer. Unexpectedly, SNAIL-driven oncogenesis was not associated with E-cadherin downregulation or induction of an overt EMT program. Instead, we show that SNAIL induces bypass of senescence and cell cycle progression through p16INK4A-independent inactivation of the Retinoblastoma (RB)-restriction checkpoint. Collectively, our work identifies non-canonical EMT-independent functions of SNAIL and unravel its complex context-dependent role in cancer.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36505-0

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DOI: 10.1038/s41467-023-36505-0

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