Title | ID1 Mediates Escape from TGFβ Tumor Suppression in Pancreatic Cancer. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Huang Y-H, Hu J, Chen F, Lecomte N, Basnet H, David CJ, Witkin MD, Allen PJ, Leach SD, Hollmann TJ, Iacobuzio-Donahue CA, Massagué J |
Journal | Cancer Discov |
Date Published | 2019 Oct 03 |
ISSN | 2159-8290 |
Abstract | TGFβ is an important tumor suppressor in pancreatic ductal adenocarcinoma (PDA), yet inactivation of TGFβ pathway components occurs in only half of PDA cases. TGFβ 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 TGFβ pathway intact avert this apoptotic effect via ID1. 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 TGFβ-mediated repression of . The sustained expression of uncouples EMT from apoptosis in PDA progenitors. AKT signaling and mechanisms linked to low-frequency genetic events converge on 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 TGFβ-induced tumor suppression without inactivating the TGFβ pathway. We report that expression is selected for in PDAs and that ID1 uncouples TGFβ-induced EMT from apoptosis. ID1 thus emerges as a crucial regulatory node and a target of interest in PDA. |
DOI | 10.1158/2159-8290.CD-19-0529 |
Alternate Journal | Cancer Discov |
PubMed ID | 31582374 |
Grant List | F30 CA203238 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States R35 CA220508 / CA / NCI NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States |
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