TGF- is a major tumor suppressor in gastrointestinal (GI) and squamous carcinomas, which exhibit frequent genetic inactivation of Smad4, a key TGF- signaling component. Apoptosis is implicated as an important mediator of the tumor suppressive function of TGF-, although this process remains poorly understood. To address this long-standing question, we dissected the tumor suppressive action of TGF- in nave pancreatic ductal adenocarcinoma (PDA) cells. Here we show that TGF-/Smad4 signaling triggers an EMT in Kras-mutant pancreatic progenitor cells but turns this process into a trigger of apoptosis by converting the progenitor cell transcription factor Sox4 from an enforcer of epithelial progenitor identity into an activator of apoptosis. This occurs as a result of the EMT-linked repression of the endodermal master regulator Klf5, which cooperates with Sox4 to promote epithelial progenitor identity, and loss of which unmasks a latent apoptotic transcriptional program driven by Sox4. By losing Smad4, Kras-mutant PDA cells avoid this fate and instead use Sox4 as a TGF--dependent enforcer of the epithelial progenitor cell state. SOURCE: Yilong Zou (zouy@mskcc.org) -  Memorial Sloan Kettering Cancer Center

Pluto Bioinformatics

GSE72069: TGF- Tumor Suppression Through A Lethal EMT