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Research Articles

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

Yun-Han Huang, Jing Hu, Fei Chen, Nicolas Lecomte, Harihar Basnet, Charles J. David, Matthew D. Witkin, Peter J Allen, Steven D Leach, Travis J Hollmann, Christine A Iacobuzio-Donahue and Joan Massague
Yun-Han Huang
Cancer Bilogy and Genetics, Memorial Sloan Kettering Cancer Center
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Jing Hu
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
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Fei Chen
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
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Nicolas Lecomte
David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center
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Harihar Basnet
Cancer Bilogy and Genetics, Memorial Sloan Kettering Cancer Center
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Charles J. David
Department of Basic Medical Sciences, Tsinghua University School of Medicine
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Matthew D. Witkin
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center
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  • ORCID record for Matthew D. Witkin
Peter J Allen
Surgery, Duke University
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Steven D Leach
Geisel School of Medicine at Dartmouth, Norton Cotton Cancer Center
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Travis J Hollmann
Pathology, Memorial Sloan Kettering Cancer Center
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Christine A Iacobuzio-Donahue
The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center
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  • ORCID record for Christine A Iacobuzio-Donahue
Joan Massague
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
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  • For correspondence: j-massague@ski.mskcc.org
DOI: 10.1158/2159-8290.CD-19-0529
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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.

  • Received May 7, 2019.
  • Revision received August 27, 2019.
  • Accepted September 30, 2019.
  • Copyright ©2019, American Association for Cancer Research.

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Published OnlineFirst October 3, 2019
doi: 10.1158/2159-8290.CD-19-0529

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ID1 mediates escape from TGF-β tumor suppression in pancreatic cancer
Yun-Han Huang, Jing Hu, Fei Chen, Nicolas Lecomte, Harihar Basnet, Charles J. David, Matthew D. Witkin, Peter J Allen, Steven D Leach, Travis J Hollmann, Christine A Iacobuzio-Donahue and Joan Massague
Cancer Discov October 3 2019 DOI: 10.1158/2159-8290.CD-19-0529

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ID1 mediates escape from TGF-β tumor suppression in pancreatic cancer
Yun-Han Huang, Jing Hu, Fei Chen, Nicolas Lecomte, Harihar Basnet, Charles J. David, Matthew D. Witkin, Peter J Allen, Steven D Leach, Travis J Hollmann, Christine A Iacobuzio-Donahue and Joan Massague
Cancer Discov October 3 2019 DOI: 10.1158/2159-8290.CD-19-0529
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