ID1 mediates escape from TGF-β tumor suppression in pancreatic cancer
Menée à l'aide de xénogreffes sur des modèles murins et à l'aide d'échantillons tumoraux et d'échantillons sains prélevés sur des patients atteints d'un cancer du pancréas, cette étude met en évidence un mécanisme par lequel l'inhibiteur de différenciation ID1 favorise l'échappement des cellules cancéreuses au facteur TGF-bêta, un suppresseur de tumeurs
TGF-β is an important tumor suppressor in pancreatic ductal adenocarcinoma (PDA), yet inactivation of TGF-β pathway components occurs in only half of PDA cases. TGF-β cooperates with oncogenic RAS signaling to trigger epithelial-mesenchymal transition (EMT) in pre-malignant 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-β pathway intact avert this apoptotic effect via Inhibitor of Differentiation 1 (ID1). ID1 family members are expressed in PDA progenitor cells and are components of a set of core transcriptional regulators shared by PDAs. PDA progression selects against TGF-β-mediated repression of ID1. The sustained expression of ID1 uncouples EMT from apoptosis in PDA progenitors. AKT signaling and mechanisms linked to low-frequency genetic events converge on ID1 to preserve its expression in PDA. Our results identify ID1 as a crucial node and potential therapeutic target in PDA.
Cancer Discovery 2019