ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis |
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Authors: | Lidong Wang Huibin Yang Ethan V Abel Gina M Ney Phillip L Palmbos Filip Bednar Yaqing Zhang Jacob Leflein Meghna Waghray Scott Owens John E Wilkinson Jayendra Prasad Mats Ljungman Andrew D Rhim Marina Pasca di Magliano Diane M Simeone |
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Institution: | 1.Department of Surgery.;2.Translational Oncology Program.;3.Department of Pediatrics.;4.Department of Internal Medicine.;5.Department of Pathology.;6.Department of Laboratory Animal Medicine.;7.Department of Radiation Oncology.;8.Department of Molecular and Integrative Physiology.;9.Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA |
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Abstract: | The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of β-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT. |
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Keywords: | pancreatic ductal adenocarcinoma metastasis epithelial– mesenchymal transition |
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