title: ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis.
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.
authors.affiliation: Department of Surgery, Translational Oncology Program.
authors.forename: Lidong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Surgery, Translational Oncology Program.
authors.forename: Huibin
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Surgery, Translational Oncology Program.
authors.forename: Ethan V
authors.initials: EV
authors.lastname: Abel
authors.affiliation: Translational Oncology Program, Department of Pediatrics.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Ney
authors.affiliation: Translational Oncology Program, Department of Internal Medicine.
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Palmbos
authors.affiliation: Department of Surgery.
authors.forename: Filip
authors.initials: F
authors.lastname: Bednar
authors.affiliation: Department of Surgery.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Translational Oncology Program.
authors.forename: Jacob
authors.initials: J
authors.lastname: Leflein
authors.affiliation: Department of Surgery, Translational Oncology Program.
authors.forename: Meghna
authors.initials: M
authors.lastname: Waghray
authors.affiliation: Department of Pathology.
authors.forename: Scott
authors.initials: S
authors.lastname: Owens
authors.affiliation: Department of Laboratory Animal Medicine.
authors.forename: John E
authors.initials: JE
authors.lastname: Wilkinson
authors.affiliation: Translational Oncology Program, Department of Radiation Oncology, Department of Molecular and Integrative Physiology.
authors.forename: Jayendra
authors.initials: J
authors.lastname: Prasad
authors.affiliation: Translational Oncology Program, Department of Radiation Oncology, Department of Molecular and Integrative Physiology.
authors.forename: Mats
authors.initials: M
authors.lastname: Ljungman
authors.affiliation: Department of Internal Medicine.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rhim
authors.affiliation: Department of Surgery, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Pasca di Magliano
authors.affiliation: Department of Surgery, Translational Oncology Program, Department of Molecular and Integrative Physiology, simeone@med.umich.edu.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000503:physiopathology*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000503:physiopathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D051741:Kruppel-Like Transcription Factors; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; C550082:TRIM29 protein, mouse; D014157:Transcription Factors; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: epithelial–mesenchymal transition; metastasis; pancreatic ductal adenocarcinoma