title: The pancreatitis-associated protein VMP1, a key regulator of inducible autophagy, promotes Kras(G12D)-mediated pancreatic cancer initiation.
abstract: Both clinical and experimental evidence have firmly established that chronic pancreatitis, in particular in the context of Kras oncogenic mutations, predisposes to pancreatic ductal adenocarcinoma (PDAC). However, the repertoire of molecular mediators of pancreatitis involved in Kras-mediated initiation of pancreatic carcinogenesis remains to be fully defined. In this study we demonstrate a novel role for vacuole membrane protein 1 (VMP1), a pancreatitis-associated protein critical for inducible autophagy, in the regulation of Kras-induced PDAC initiation. Using a newly developed genetically engineered model, we demonstrate that VMP1 increases the ability of Kras to give rise to preneoplastic lesions, pancreatic intraepithelial neoplasias (PanINs). This promoting effect of VMP1 on PanIN formation is due, at least in part, by an increase in cell proliferation combined with a decrease in apoptosis. Using chloroquine, an inhibitor of autophagy, we show that this drug antagonizes the effect of VMP1 on PanIN formation. Thus, we conclude that VMP1-mediated autophagy cooperate with Kras to promote PDAC initiation. These findings are of significant medical relevance, molecules targeting autophagy are currently being tested along chemotherapeutic agents to treat PDAC and other tumors in human trials.
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: C
authors.initials: C
authors.lastname: Loncle
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: M I
authors.initials: MI
authors.lastname: Molejon
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: S
authors.initials: S
authors.lastname: Lac
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: J I
authors.initials: JI
authors.lastname: Tellechea
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic, Rochester, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lomberk
authors.affiliation: Department of Surgery, University of Cordoba, Cordoba, Argentine.
authors.forename: L
authors.initials: L
authors.lastname: Gramatica
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Fernandez Zapico
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: N
authors.initials: N
authors.lastname: Dusetti
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic, Rochester, USA.
authors.forename: R
authors.initials: R
authors.lastname: Urrutia
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Iovanna
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D044584:Carcinoma, Ductal / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000073718:Pancreatitis-Associated Proteins; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008164:Luminescent Proteins; D008565:Membrane Proteins; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; C000623277:VMP1 protein, mouse; C413663:fluorescent protein 583; D002738:Chloroquine; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)