ID1 mediates escape from TGF-β tumor suppression in pancreatic cancer.

TGF beta is an important tumor suppressor in pancreatic ductal adenocarcinoma (PDA), yet inactivation of TGF beta pathway components occurs in only half of PDA cases. TGF beta cooperates with oncogenic RAS signaling to trigger epithelial-to-mesenchymal transition (EMT) in premalignant pancreatic epithelial progenitors, which is coupled to apoptosis owing to an imbalance of SOX4 and KLF5 transcription factors. We report that PDAs that develop with the TGF beta pathway intact avert this apoptotic effect via 101. 101 family members are expressed in PDA progenitor cells and encode components of a set of core transcriptional regulators shared by PDAs. PDA progression selects against TGF beta-mediated repression of 101. The sustained expression of 101 uncouples EMT from apoptosis in PDA progenitors. AKT signaling and mechanisms linked to low-frequency genetic events converge on 101 to preserve its expression in PDA. Our results identify ID1 as a crucial node and potential therapeutic target in PDA. SIGNIFICANCE: Half of PDAs escape TGF beta-induced tumor suppression without inactivating the TGF beta pathway. We report that 101 expression is selected for in PDAs and that ID1 uncouples TGF beta -induced EMT from apoptosis. 101 thus emerges as a crucial regulatory node and a target of interest in PDA.