TGF-? Tumor Suppression through a Lethal EMT.

ABSTRACT: TGF-? signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-? mediator Smad4. We show that TGF-? induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-?-sensitive PDA cells, EMT becomes lethal by converting TGF-?-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-?. TGF-?-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-? tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.

SUBMITTER: David CJ 

PROVIDER: S-EPMC4801341 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature