TGF-β Tumor Suppression Through a Lethal EMT

Cell. 2016 Feb 25;164(5):1015-30. doi: 10.1016/j.cell.2016.01.009. Epub 2016 Feb 18.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Animals
  • Apoptosis
  • Carcinoma, Ductal / genetics*
  • Carcinoma, Ductal / pathology
  • Epithelial-Mesenchymal Transition*
  • Gene Regulatory Networks*
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Organoids / metabolism
  • Organoids / pathology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • SOXC Transcription Factors / metabolism
  • Smad4 Protein / metabolism
  • Transforming Growth Factor beta / antagonists & inhibitors*

Substances

  • Klf5 protein, mouse
  • Kruppel-Like Transcription Factors
  • SOXC Transcription Factors
  • Smad4 Protein
  • Smad4 protein, mouse
  • Sox4 protein, mouse
  • Transforming Growth Factor beta