title: The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma.
abstract: Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, United States.
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Krah
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, United States.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: De La O
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Galvin H
authors.initials: GH
authors.lastname: Swift
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Chinh Q
authors.initials: CQ
authors.lastname: Hoang
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States.
authors.forename: Spencer G
authors.initials: SG
authors.lastname: Willet
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States.
authors.forename: Fong
authors.initials: F
authors.lastname: Chen Pan
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, United States.
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Cash
authors.affiliation: Department of Pathology, Huntsman Cancer Hospital, University of Utah, Salt Lake City, United States.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Bronner
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States.
authors.forename: Christopher Ve
authors.initials: CV
authors.lastname: Wright
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: MacDonald
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, United States.
authors.forename: L Charles
authors.initials: LC
authors.lastname: Murtaugh
mesh_terms: D061354:Acinar Cells / Q000502:physiology*; D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D002278:Carcinoma in Situ / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D054338:Cell Transdifferentiation; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D014157:Transcription Factors / Q000032:analysis* / Q000235:genetics
chemical_list: D014157:Transcription Factors; C062602:transcription factor PTF1
keywords: developmental biology; differentiation; human; human biology; medicine; mouse; pancreatic cancer; pancreatitis; stem cells