title: Pten constrains centroacinar cell expansion and malignant transformation in the pancreas.
abstract: To determine the role of the phosphatidylinositol 3-kinase (PI3-K) pathway in pancreas development, we generated a pancreas-specific knockout of Pten, a negative regulator of PI3-K signaling. Knockout mice display progressive replacement of the acinar pancreas with highly proliferative ductal structures that contain abundant mucins and express Pdx1 and Hes1, two markers of pancreatic progenitor cells. Moreover, a fraction of these mice develop ductal malignancy. We provide evidence that ductal metaplasia results from the expansion of centroacinar cells rather than transdifferentiation of acinar cells. These results indicate that Pten actively maintains the balance between different cell types in the adult pancreas and that misregulation of the PI3-K pathway in centroacinar cells may contribute to the initiation of pancreatic carcinoma in vivo.
authors.affiliation: Howard Hughes Medical Institute and the Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
authors.forename: Bangyan
authors.initials: B
authors.lastname: Stiles
authors.forename: Gregory Y
authors.initials: GY
authors.lastname: Lauwers
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Michael
authors.initials: M
authors.lastname: Mendoza
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Amy
authors.initials: A
authors.lastname: Greenwood
authors.forename: Kuang-hung
authors.initials: KH
authors.lastname: Cheng
authors.forename: Margaret
authors.initials: M
authors.lastname: McLaughlin
authors.forename: Dennis
authors.initials: D
authors.lastname: Brown
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Depinho
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Melton
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D008679:Metaplasia / Q000473:pathology; D051379:Mice; D051059:PTEN Phosphohydrolase; D010179:Pancreas / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000517:prevention & control; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D025521:Tumor Suppressor Proteins; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse