title: TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells.
abstract: Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases.
authors.affiliation: Departments of Cellular and Structural Biology, University of Texas Heath Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Departments of Cellular and Structural Biology, University of Texas Heath Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Akanuma
authors.affiliation: Surgery Department, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Chengyang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Surgery Department, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.affiliation: Transplant Centre, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Halff
authors.affiliation: Transplant Centre, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Washburn
authors.affiliation: Departments of Cellular and Structural Biology, University of Texas Heath Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Luzhe
authors.initials: L
authors.lastname: Sun
authors.affiliation: Departments of Cellular and Structural Biology, University of Texas Heath Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
mesh_terms: D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D006801:Humans; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology*; D046790:Pancreas, Exocrine / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D053773:Transforming Growth Factor beta1