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Apoptosis is implicated as an important mediator of the tumor suppressive function of TGF-β, although this process remains poorly understood. To address this long-standing question, we dissected the tumor suppressive action of TGF-β in naïve pancreatic ductal adenocarcinoma (PDA) cells. Here we show that TGF-β/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-β-dependent enforcer of the epithelial progenitor cell state. Overall design: In this study, 16 RNA-Seq samples and 6 ChIP-Seq samples are included.</long_description><repository>ENA</repository></additional><is_claimable>false</is_claimable><name>Mus musculus</name><description>TGF-β Tumor Suppression Through A Lethal EMT</description><dates><last_updated>2025-09-24</last_updated><first_public>2016-10-10</first_public></dates><accession>PRJNA292864</accession><cross_references><GEO>GSE72069</GEO><taxon>10090</taxon><PubMed>26898331</PubMed></cross_references></HashMap>