| First Author | David CJ | Year | 2016 |
| Journal | Cell | Volume | 164 |
| Issue | 5 | Pages | 1015-30 |
| PubMed ID | 26898331 | Mgi Jnum | J:230802 |
| Mgi Id | MGI:5766082 | Doi | 10.1016/j.cell.2016.01.009 |
| Citation | David CJ, et al. (2016) TGF-beta Tumor Suppression through a Lethal EMT. Cell 164(5):1015-30 |
| abstractText | TGF-beta 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-beta mediator Smad4. We show that TGF-beta induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-beta-sensitive PDA cells, EMT becomes lethal by converting TGF-beta-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-beta. TGF-beta-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-beta tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network. |
