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dc.contributor.author | Quilichini, Evans | |
dc.contributor.author | Fabre, Mélanie | |
dc.contributor.author | Dirami, Thassadite | |
dc.contributor.author | Stedman, Aline | |
dc.contributor.author | De Vas, Matias | |
dc.contributor.author | Ozguc, Ozge | |
dc.contributor.author | Pasek, Raymond C | |
dc.contributor.author | Cereghini, Silvia | |
dc.contributor.author | Morillon, Lucie | |
dc.contributor.author | Guerra, Carmen | |
dc.contributor.author | Couvelard, Anne | |
dc.contributor.author | Gannon, Maureen | |
dc.contributor.author | Haumaitre, Cécile | |
dc.date.accessioned | 2019-07-02T08:46:25Z | |
dc.date.available | 2019-07-02T08:46:25Z | |
dc.date.issued | 2019-06-20 | |
dc.identifier.citation | Cell Mol Gastroenterol Hepatol. 2019 . pii: S2352-345X(19)30084-0 | es_ES |
dc.identifier.issn | 2352345X | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/7837 | |
dc.description.abstract | BACKGROUND AND AIMS: The exocrine pancreas consists of acinar cells that produce digestive enzymes transported to the intestine through a branched ductal epithelium. Chronic pancreatitis is characterized by progressive inflammation, fibrosis and loss of acinar tissue. These changes of the exocrine tissue are risk factors for pancreatic cancer. The cause of chronic pancreatitis cannot be identified in one-quarter of patients. Here, we investigated how duct dysfunction could contribute to pancreatitis development. METHODS: The transcription factor Hnf1b, first expressed in pancreatic progenitors, is strictly restricted to ductal cells from late embryogenesis. We have previously shown that Hnf1b is crucial for pancreas morphogenesis but its postnatal role still remains unelucidated. To investigate the role of pancreatic ducts in exocrine homeostasis, we inactivated Hnf1b gene in vivo in mouse ductal cells. RESULTS: We uncovered that postnatal Hnf1b inactivation in pancreatic ducts leads to chronic pancreatitis in adults. Hnf1bΔduct mutants display dilatation of ducts, loss of acinar cells, acinar-to-ductal metaplasia (ADM) and lipomatosis. We deciphered the early events involved, with downregulation of cystic disease-associated genes, loss of primary cilia, upregulation of signaling pathways, especially Yap pathway involved in ADM. Remarkably, Hnf1bΔduct mutants developed pancreatic intraepithelial neoplasia and promote PanIN progression in concert with KRAS. We further showed that adult Hnf1b inactivation in pancreatic ducts is associated with impaired regeneration after injury, with persistent metaplasia and initiation of neoplasia. CONCLUSION: Loss of Hnf1b in ductal cells leads to chronic pancreatitis and neoplasia. This reveals that Hnf1b deficiency may contribute to diseases of the exocrine pancreas and could gain further insight into the etiology of pancreatitis and tumorigenesis. | es_ES |
dc.description.sponsorship | Support to CH was received from theCentre National de la Recherche Scientifique (CNRS), the Universite Pierre et Marie Curie (UPMC)- Sorbonne Université , the GEFLUC - Les entreprises contre le Cancer, the Societe Francophone du Diabete (SFD)-Ypsomed, the programme Emergence UPMC. EQ was supported by a PhD fellowship from the French Ministère de la Recherche et de la Technologie. MF is an assistant engineer of the CNRS. TD and AS were supported by Sorbonne Université. MDV was supported by a PhD student fellowship from the European Marie Curie Initial Training Network (ITN)-Biology of Liver and Pancreatic Development and Disease (BOLD). O. O. was supported by a Master1 fellowship. RCP was supported by a postdoctoral fellowship from the American Heart Association (14POST20380262). MG was supported by the National Institutes of Health (U01 DK089540) and the Juvenile Diabetes Research Foundation (1-2011-592). CH is a permanent senior researcher of the Institut National de la Sante et de la Recherche Medicale (INSERM). | es_ES |
dc.language.iso | eng | es_ES |
dc.type.hasVersion | AM | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject | Acinar-to-ductal-metaplasia | es_ES |
dc.subject | Ducts | es_ES |
dc.subject | Hnf1b | es_ES |
dc.subject | Pancreatic cancer | es_ES |
dc.subject | Pancreatitis | es_ES |
dc.title | Pancreatic ductal deletion of Hnf1b disrupts exocrine homeostasis, leads to pancreatitis and facilitates tumorigenesis | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.identifier.pubmedID | 31229598 | es_ES |
dc.identifier.doi | 10.1016/j.jcmgh.2019.06.005 | es_ES |
dc.contributor.funder | French National Centre for Scientific Research (Francia) | |
dc.contributor.funder | Sorbonne University (Francia) | |
dc.contributor.funder | Société Francophone du Diabète | |
dc.contributor.funder | American Heart Association | |
dc.contributor.funder | Juvenile Diabetes Research Foundation | |
dc.contributor.funder | Institut National de la Santé et de la Recherche Médicale (Francia) | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 2352-345X | es_ES |
dc.relation.publisherversion | https://doi.org/ 10.1016/j.jcmgh.2019.06.005. | es_ES |
dc.identifier.journal | Cellular and molecular gastroenterology and hepatology | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación::Grupo de Oncología Experimental | es_ES |
dc.rights.accessRights | open access | es_ES |