title: Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma.
abstract: Tumors are largely classified by histologic appearance, yet morphologic features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.
authors.affiliation: Departments of Pediatrics and Cellular and Molecular Medicine, University of California-San Diego, La Jolla, CA 92093-0695, USA.
authors.forename: Janel L
authors.initials: JL
authors.lastname: Kopp
authors.forename: Guido
authors.initials: G
authors.lastname: von Figura
authors.forename: Erin
authors.initials: E
authors.lastname: Mayes
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Liu
authors.forename: Claire L
authors.initials: CL
authors.lastname: Dubois
authors.forename: John P
authors.initials: JP
authors.lastname: Morris
authors.forename: Fong Cheng
authors.initials: FC
authors.lastname: Pan
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
authors.forename: Kristin
authors.initials: K
authors.lastname: Jensen
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
authors.forename: Maike
authors.initials: M
authors.lastname: Sander
mesh_terms: D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011905:Genes, ras; D006801:Humans; D008679:Metaplasia; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse