Pancreatic cancer-Associated retinoblastoma 1 dysfunction enables TGF-?beta;?to promote proliferation

A. Jesse Gore, Samantha L. Deitz, Lakshmi Reddy Palam, Kelly E. Craven, Murray Korc

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is often associated with overexpression of TGF-?. Given its tumor suppressor functions, it is unclear whether TGF-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-?1 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-receptor kinase, combined inhibition of MEK/Src or MEK/PI3K, and restoration of RB expression. TGF-?1 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-?1-induced mitogenesis was markedly attenuated by inhibition of Wnt secretion. In an in vivo syngeneic orthotopic model, inhibition of TGF-signaling suppressed KRC cell proliferation, tumor growth, stroma formation, EMT, metastasis, ascites formation, and Wnt7b expression, and markedly prolonged survival. Together, these data indicate that RB dysfunction converts TGF-to a mitogen that activates known oncogenic signaling pathways and upregulates Wnt7b, which synergize to promote PCC invasion, survival, and mitogenesis. Furthermore, this study suggests that concomitantly targeting TGF-And Wnt7b signaling in PDAC may disrupt these aberrant pathways, which warrants further evaluation in preclinical models.

Original languageEnglish (US)
Pages (from-to)338-352
Number of pages15
JournalJournal of Clinical Investigation
Volume124
Issue number1
DOIs
StatePublished - Jan 2 2014

ASJC Scopus subject areas

  • Medicine(all)

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