@article{aa6881b2da7b444ebc432c73e8cb0279,
title = "Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer",
abstract = "TGFβ is important during pancreatic ductal adenocarcinoma (PDA) progression. Canonical TGFβ signaling suppresses epithelial pancreatic cancer cell proliferation; as a result, inhibiting TGFβ has not been successful in PDA. In contrast, we demonstrate that inhibition of stromal TGFβR2 reduces IL-6 production from cancer-associated fibroblasts, resulting in a reduction of STAT3 activation in tumor cells and reversion of the immunosuppressive landscape. Up to 7% of human PDA have tumor cell-specific deficiency in canonical TGFβ signaling via loss of TGFβR2. We demonstrate that in PDA that harbors epithelial loss of TGFβR2, inhibition of TGFβ signaling is selective for stromal cells and results in a therapeutic benefit. Our study highlights the potential benefit of TGFβ blockade in PDA and the importance of stratifying PDA patients who might benefit from such therapy.",
keywords = "IL-6, TGFβ, cancer-associated fibroblast, pancreatic cancer, tumor immunology",
author = "Huocong Huang and Yuqing Zhang and Valerie Gallegos and Noah Sorrelle and Zaid, {Mohamed Medhat} and Jason Toombs and Wenting Du and Steven Wright and Moriah Hagopian and Zhaoning Wang and Hosein, {Abdel Nasser} and Sathe, {Adwait Amod} and Chao Xing and Koay, {Eugene J.} and Driscoll, {Kyla E.} and Brekken, {Rolf A.}",
note = "Funding Information: This work was supported by a sponsored research agreement from Eli Lilly & Company (SRA5200886401 RAB), NIH grants R01 (CA192381) to RAB and U54 (CA210181 Project 2) to RAB and EJK, the Effie Marie Cain Fellowship to RAB and a predoctoral fellowship from the American Heart Association, and the Harry S. Moss Heart Trust (19PRE34380436) to ZW. We thank Drs. Jason Fleming, Martin Fernandez-Zapico, and Alec Zhang for provision of cell lines and reagents. We acknowledge helpful input from Dr. Jill Westcott, other members of the Brekken laboratory and Drs. Herb Zeh, Daolin Tang, and Michael Lotze and editorial assistance provided by Dave Primm of the UTSW Department of Surgery. Funding Information: This work was supported by a sponsored research agreement from Eli Lilly & Company (SRA5200886401 RAB), NIH grants R01 (CA192381) to RAB and U54 (CA210181 Project 2) to RAB and EJK, the Effie Marie Cain Fellowship to RAB and a predoctoral fellowship from the American Heart Association, and the Harry S. Moss Heart Trust (19PRE34380436) to ZW. We thank Drs. Jason Fleming, Martin Fernandez‐Zapico, and Alec Zhang for provision of cell lines and reagents. We acknowledge helpful input from Dr. Jill Westcott, other members of the Brekken laboratory and Drs. Herb Zeh, Daolin Tang, and Michael Lotze and editorial assistance provided by Dave Primm of the UTSW Department of Surgery. Publisher Copyright: {\textcopyright} 2019 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2019",
month = nov,
day = "7",
doi = "10.15252/emmm.201910515",
language = "English (US)",
volume = "11",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "11",
}