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Cancer Discov. 2019 Oct 3. pii: CD-19-0529. doi: 10.1158/2159-8290.CD-19-0529. [Epub ahead of print]

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

Author information

1
Cancer Bilogy and Genetics, Memorial Sloan Kettering Cancer Center.
2
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center.
3
David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center.
4
Department of Basic Medical Sciences, Tsinghua University School of Medicine.
5
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center.
6
Surgery, Duke University.
7
Geisel School of Medicine at Dartmouth, Norton Cotton Cancer Center.
8
Pathology, Memorial Sloan Kettering Cancer Center.
9
The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center.
10
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center j-massague@ski.mskcc.org.

Abstract

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.

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