TGF-β tumor suppression through a lethal EMT Journal Article
| Authors: | David, C. J.; Huang, Y. H.; Chen, M.; Su, J.; Zou, Y.; Bardeesy, N.; Iacobuzio-Donahue, C. A.; Massagué, J. |
| Article Title: | TGF-β tumor suppression through a lethal EMT |
| 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. © 2016 Elsevier Inc. |
| Journal Title: | Cell |
| Volume: | 164 |
| Issue: | 5 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2016-02-25 |
| Start Page: | 1015 |
| End Page: | 1030 |
| Language: | English |
| DOI: | 10.1016/j.cell.2016.01.009 |
| PROVIDER: | scopus |
| PMCID: | PMC4801341 |
| PUBMED: | 26898331 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 April 2016 -- Source: Scopus |
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