Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer

Research output: Contribution to journalArticle

Huocong Huang, Yuqing Zhang, Valerie Gallegos, Noah Sorrelle, Mohamed Medhat Zaid, Jason Toombs, Wenting Du, Steven Wright, Moriah Hagopian, Zhaoning Wang, Abdel Nasser Hosein, Adwait Amod Sathe, Chao Xing, Eugene J. Koay, Kyla E. Driscoll, Rolf A. Brekken

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.

Original languageEnglish (US)
Article numbere10515
JournalEMBO Molecular Medicine
Volume11
Issue number11
DOIs
StatePublished - Nov 7 2019

PMID: 31609088

Altmetrics

Cite this

Standard

Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer. / 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.

In: EMBO Molecular Medicine, Vol. 11, No. 11, e10515, 07.11.2019.

Research output: Contribution to journalArticle

Harvard

Huang, H, Zhang, Y, Gallegos, V, Sorrelle, N, Zaid, MM, Toombs, J, Du, W, Wright, S, Hagopian, M, Wang, Z, Hosein, AN, Sathe, AA, Xing, C, Koay, EJ, Driscoll, KE & Brekken, RA 2019, 'Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer' EMBO Molecular Medicine, vol. 11, no. 11, e10515. https://doi.org/10.15252/emmm.201910515

APA

Huang, H., Zhang, Y., Gallegos, V., Sorrelle, N., Zaid, M. M., Toombs, J., ... Brekken, R. A. (2019). Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer. EMBO Molecular Medicine, 11(11), [e10515]. https://doi.org/10.15252/emmm.201910515

Vancouver

Huang H, Zhang Y, Gallegos V, Sorrelle N, Zaid MM, Toombs J et al. Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer. EMBO Molecular Medicine. 2019 Nov 7;11(11). e10515. https://doi.org/10.15252/emmm.201910515

Author

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. / Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer. In: EMBO Molecular Medicine. 2019 ; Vol. 11, No. 11.

BibTeX

@article{f9fc1eaa00034d699403ec3ee16f753c,
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 = "cancer-associated fibroblast, IL-6, pancreatic cancer, TGFβ, 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.}",
year = "2019",
month = "11",
day = "7",
doi = "10.15252/emmm.201910515",
language = "English (US)",
volume = "11",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley",
number = "11",

}

RIS

TY - JOUR

T1 - Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer

AU - Huang, Huocong

AU - Zhang, Yuqing

AU - Gallegos, Valerie

AU - Sorrelle, Noah

AU - Zaid, Mohamed Medhat

AU - Toombs, Jason

AU - Du, Wenting

AU - Wright, Steven

AU - Hagopian, Moriah

AU - Wang, Zhaoning

AU - Hosein, Abdel Nasser

AU - Sathe, Adwait Amod

AU - Xing, Chao

AU - Koay, Eugene J.

AU - Driscoll, Kyla E.

AU - Brekken, Rolf A.

PY - 2019/11/7

Y1 - 2019/11/7

N2 - 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.

AB - 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.

KW - cancer-associated fibroblast

KW - IL-6

KW - pancreatic cancer

KW - TGFβ

KW - tumor immunology

UR - http://www.scopus.com/inward/record.url?scp=85074303641&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074303641&partnerID=8YFLogxK

U2 - 10.15252/emmm.201910515

DO - 10.15252/emmm.201910515

M3 - Article

VL - 11

JO - EMBO Molecular Medicine

T2 - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

IS - 11

M1 - e10515

ER -

ID: 54973350