Journal Article

DKFZ-2023-00462

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Non-canonical functions of SNAIL drive context-specific cancer progression.

Paul, M. C.DKFZ* ; Schneeweis, C.DKFZ* ; Falcomatà, C.DKFZ* ; Shan, C.DKFZ* ; Rossmeisl, D.DKFZ* ; Koutsouli, S. ; Klement, C.DKFZ* ; Zukowska, M.DKFZ* ; Widholz, S.DKFZ* ; Jesinghaus, M.DKFZ* ; Heuermann, K. K.DKFZ* ; Engleitner, T.DKFZ* ; Seidler, B.DKFZ* ; Sleiman, K.DKFZ* ; Steiger, K. ; Tschurtschenthaler, M.DKFZ* ; Walter, B. ; Weidemann, S. A.DKFZ* ; Pietsch, R.DKFZ* ; Schnieke, A. ; Schmid, R. M. ; Robles, M. S. ; Andrieux, G.DKFZ* ; Börries, M.DKFZ* ; Rad, R.DKFZ* ; Schneider, G.DKFZ* ; Saur, D. K. M.DKFZ*

2023
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-023-36505-0

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.

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Contributing Institute(s):

1. DKTK Koordinierungsstelle München (MU01)
2. DKTK Koordinierungsstelle Freiburg (FR01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

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