Project description: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 novel non-canonical EMT-independent functions of SNAIL and unravel its complex context-dependent role in cancer.
Project description:The epithelial-to-mesenchymal transition (EMT) is a critical biological process in normal development and tumor progression. One of the EMT regulator, Snail is shown to suppress or activate its downstream genes to sustain migratory capacities while remodeling the tumor microenvironment. Identification of the Snail-regulated transcriptome through a robust sequencing technique will give a global direction for targeting Snail-driven malignancy.