TGF-β Tumor Suppression through a Lethal EMT

Charles J. David, Yun Han Huang, Mo Chen, Jie Su, Yilong Zou, Nabeel Bardeesy, Christine A. Iacobuzio-Donahue, Joan Massagué

Research output: Contribution to journalArticlepeer-review

Abstract

Summary TGF-β 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-β mediator Smad4. We show that TGF-β induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-β-sensitive PDA cells, EMT becomes lethal by converting TGF-β-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-β. TGF-β-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-β tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.

Original languageEnglish (US)
Pages (from-to)1015-1030
Number of pages16
JournalCell
Volume164
Issue number5
DOIs
StatePublished - Feb 25 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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