Open AccessTargeting TGF βR2‐mutant tumors exposes vulnerabilities to stromal TGF β blockade in pancreatic cancer
Author(s) -
Huang Huocong,
Zhang Yuqing,
Gallegos Valerie,
Sorrelle Noah,
Zaid Mohamed Medhat,
Toombs Jason,
Du Wenting,
Wright Steven,
Hagopian Moriah,
Wang Zhaoning,
Hosein Abdel Nasser,
Sathe Adwait Amod,
Xing Chao,
Koay Eugene J,
Driscoll Kyla E,
Brekken Rolf A
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201910515
Subject(s) - transforming growth factor , pancreatic cancer , stromal cell , blockade , cancer research , mutant , biology , cancer , medicine , immunology , microbiology and biotechnology , receptor , gene , genetics
TGF β is important during pancreatic ductal adenocarcinoma ( PDA ) progression. Canonical TGF β signaling suppresses epithelial pancreatic cancer cell proliferation; as a result, inhibiting TGF β has not been successful in PDA . In contrast, we demonstrate that inhibition of stromal TGF βR2 reduces IL ‐6 production from cancer‐associated fibroblasts, resulting in a reduction of STAT 3 activation in tumor cells and reversion of the immunosuppressive landscape. Up to 7% of human PDA have tumor cell‐specific deficiency in canonical TGF β signaling via loss of TGF βR2. We demonstrate that in PDA that harbors epithelial loss of TGF βR2, inhibition of TGF β signaling is selective for stromal cells and results in a therapeutic benefit. Our study highlights the potential benefit of TGF β blockade in PDA and the importance of stratifying PDA patients who might benefit from such therapy.