Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation

The Journal of Clinical Investigation
A Jesse GoreMurray Korc

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is often associated with overexpression of TGF-β. Given its tumor suppressor functions, it is unclear whether TGF-β is a valid therapeutic target for PDAC. Here, we found that proliferating pancreatic cancer cells (PCCs) from human PDAC patients and multiple murine models of PDAC (mPDAC) often exhibit abundant levels of phosphorylated retinoblastoma 1 (RB) and Smad2. TGF-β1 treatment enhanced proliferation of PCCs isolated from KrasG12D-driven mPDAC that lacked RB (KRC cells). This mitogenic effect was abrogated by pharmacological inhibition of type I TGF-β receptor kinase, combined inhibition of MEK/Src or MEK/PI3K, and restoration of RB expression. TGF-β1 promoted epithelial-to-mesenchymal transition (EMT), invasion, Smad2/3 phosphorylation, Src activation, Wnt reporter activity, and Smad-dependent upregulation of Wnt7b in KRC cells. Importantly, TGF-β1-induced mitogenesis was markedly attenuated by inhibition of Wnt secretion. In an in vivo syngeneic orthotopic model, inhibition of TGF-β signaling suppressed KRC cell proliferation, tumor growth, stroma formation, EMT, metastasis, ascites formation, and Wnt7b expression, and markedly prolonged survival. Together, these data indicate tha...Continue Reading

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Citations

Oct 16, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Xin-Hong WangBao-Xin Li
Jun 18, 2014·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Lingyu LuoDeqiang Huang
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Jul 10, 2019·Artificial Cells, Nanomedicine, and Biotechnology·Xiulian XiaXiaolan Yu
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Jul 28, 2016·The Journal of Clinical Investigation·Murray Korc
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Jul 7, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ming LiFeng Wang-Johanning
Aug 3, 2021·Evidence-based Complementary and Alternative Medicine : ECAM·Yun YangWen-Juan Gan

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Datasets Mentioned

BETA
E-MEXP-3988

Methods Mentioned

BETA
transfection
PCR
ChIP

Software Mentioned

ImageProPlus
Sigma Plot
GSEA
ImageJ
Vevo2100 System
HUGO
Systat

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