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, Dieter Saur
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.