Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer.,EMBO Molecular Medicine

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Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer.
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2019-10-14 , DOI: 10.15252/emmm.201910515
Huocong Huang ₁ , Yuqing Zhang _{1,

2} , Valerie Gallegos ₃ , Noah Sorrelle ₁ , Mohamed Medhat Zaid ₄ , Jason Toombs ₁ , Wenting Du _{1,

2} , Steven Wright ₁ , Moriah Hagopian ₅ , Zhaoning Wang ₆ , Abdel Nasser Hosein ₇ , Adwait Amod Sathe ₈ , Chao Xing ₈ , Eugene J Koay ₄ , Kyla E Driscoll ₉ , Rolf A Brekken _{1,

2,

5}

Affiliation

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.

中文翻译：

靶向TGFβR2突变的肿瘤使胰腺癌易受基质TGFβ阻断。

TGFβ在胰腺导管腺癌（PDA）进程中很重要。典型的TGFβ信号传导抑制上皮胰腺癌细胞的增殖；结果，抑制TGFβ在PDA中没有成功。相比之下，我们证明了基质TGFβR2的抑制作用降低了癌症相关成纤维细胞的IL-6产生，导致肿瘤细胞中STAT3激活的减少和免疫抑制格局的逆转。高达7％的人PDA通过TGFβR2的缺失而在正常的TGFβ信号传导中具有肿瘤细胞特异性缺陷。我们证明在具有TGFβR2上皮丢失的PDA中，对TGFβ信号的抑制对基质细胞具有选择性，并产生治疗益处。

更新日期：2019-11-07

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