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

Paul, Mariel C; Schneeweis, Christian; Falcomatà, Chiara; Shan, Chuan; Rossmeisl, Daniel; Koutsouli, Stella; Klement, Christine; Zukowska, Magdalena; Widholz, Sebastian A; Jesinghaus, Moritz; Heuermann, Konstanze K; Engleitner, Thomas; Seidler, Barbara; Sleiman, Katia; Steiger, Katja; Tschurtschenthaler, Markus; Walter, Benjamin; Weidemann, Sören A; Pietsch, Regina; Schnieke, Angelika; Schmid, Roland M; Robles, Maria S; Andrieux, Geoffroy; Boerries, Melanie; Rad, Roland; Schneider, Günter; Saur, Dieter     «

Paul, Mariel C; Schneeweis, Christian; Falcomatà, Chiara; Shan, Chuan; Rossmeisl, Daniel; Koutsouli, Stella; Klement, Christine; Zukowska, Magdalena; Widholz, Sebastian A; Jesinghaus, Moritz; Heuermann, Konstanze K; Engleitner, Thomas; Seidler, Barbara; Sleiman, Katia; Steiger, Katja; Tschurtschenthaler, Markus; Walter, Benjamin; Weidemann, Sören A; Pietsch, Regina; Schnieke, Angelika; Schmid, Roland M; Robles, Maria S; Andrieux, Geoffroy; Boerries, Melanie; Rad, Roland; Schneider, Günter; 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.      «

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, ra...     »