2024-03-28T11:00:40Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/78372023-08-31T07:24:06Zcom_20.500.12105_2174com_20.500.12105_2051com_20.500.12105_2173col_20.500.12105_2175
Repisalud
author
Quilichini, Evans
author
Fabre, Mélanie
author
Dirami, Thassadite
author
Stedman, Aline
author
De Vas, Matias
author
Ozguc, Ozge
author
Pasek, Raymond C
author
Cereghini, Silvia
author
Morillon, Lucie
author
Guerra, Carmen
author
Couvelard, Anne
author
Gannon, Maureen
author
Haumaitre, Cécile
funder
French National Centre for Scientific Research (Francia)
funder
Sorbonne University (Francia)
funder
Société Francophone du Diabète
funder
American Heart Association
funder
Juvenile Diabetes Research Foundation
funder
Institut National de la Santé et de la Recherche Médicale (Francia)
2019-07-02T08:46:25Z
2019-07-02T08:46:25Z
2019-06-20
Cell Mol Gastroenterol Hepatol. 2019 . pii: S2352-345X(19)30084-0
2352345X
http://hdl.handle.net/20.500.12105/7837
31229598
10.1016/j.jcmgh.2019.06.005
2352-345X
Cellular and molecular gastroenterology and hepatology
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.
eng
Acinar-to-ductal-metaplasia
Ducts
Hnf1b
Pancreatic cancer
Pancreatitis
Pancreatic ductal deletion of Hnf1b disrupts exocrine homeostasis, leads to pancreatitis and facilitates tumorigenesis
journal article
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URL
https://repisalud.isciii.es/bitstream/20.500.12105/7837/1/PancreaticductaldeletionofHnf1b_2019.pdf
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PancreaticductaldeletionofHnf1b_2019.pdf
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https://repisalud.isciii.es/bitstream/20.500.12105/7837/7/PancreaticductaldeletionofHnf1b_2019.pdf.txt
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PancreaticductaldeletionofHnf1b_2019.pdf.txt