title: Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia.
abstract: The transdifferentiation of pancreatic acinar cells to a ductal phenotype (acinar-to-ductal metaplasia, ADM) occurs after injury or inflammation of the pancreas and is a reversible process. However, in the presence of activating Kras mutations or persistent epidermal growth factor receptor (EGF-R) signalling, cells that underwent ADM can progress to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic cancer. In transgenic animal models, ADM and PanINs are initiated by high-affinity ligands for EGF-R or activating Kras mutations, but the underlying signalling mechanisms are not well understood. Here, using a conditional knockout approach, we show that protein kinase D1 (PKD1) is sufficient to drive the reprogramming process to a ductal phenotype and progression to PanINs. Moreover, using 3D explant culture of primary pancreatic acinar cells, we show that PKD1 acts downstream of TGFα and Kras, to mediate formation of ductal structures through activation of the Notch pathway.
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Geou-Yarh
authors.initials: GY
authors.lastname: Liou
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Döppler
authors.affiliation: The Biotechnology Centre of Oslo, University of Oslo, N-0349 Oslo, Norway.
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Braun
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Panayiotou
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Scotti Buzhardt
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Radisky
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Fields
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Murray
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Q Jane
authors.initials: QJ
authors.lastname: Wang
authors.affiliation: The Biotechnology Centre of Oslo, University of Oslo, N-0349 Oslo, Norway.
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Storz
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D002278:Carcinoma in Situ / Q000201:enzymology* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D065150:Cellular Reprogramming / Q000187:drug effects; D018450:Disease Progression; D008810:Mice, Inbred C57BL; D010183:Pancreatic Ducts / Q000187:drug effects / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051880:Receptors, Notch; D016211:Transforming Growth Factor alpha; C089212:protein kinase D; D011493:Protein Kinase C; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)