title: Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation.
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 that RB dysfunction converts TGF-β 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-β and Wnt7b signaling in PDAC may disrupt these aberrant pathways, which warrants further evaluation in preclinical models.
authors: A Jesse
authors: AJ
authors: Gore
authors: Samantha L
authors: SL
authors: Deitz
authors: Lakshmi Reddy
authors: LR
authors: Palam
authors: Kelly E
authors: KE
authors: Craven
authors: Murray
authors: M
authors: Korc
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011725:Pyridines / Q000494:pharmacology; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays
chemical_list: C519132:2-(5-benzo(1,3)dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride; D052117:Benzodioxoles; D007093:Imidazoles; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; D016160:Retinoblastoma Protein; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C490675:WNT7B protein, human; D051153:Wnt Proteins