In:
Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 10_Supplement ( 2020-10-01), p. A05-A05
Abstract:
Vps34 is the only member of class III of phosphoinositide-3-kinases (PI3Ks) and the main producer of phosphatidylinositol-3-monophosphate (PI3P), a lipid involved in regulating intracellular vesicular trafficking. Vps34 and its regulatory subunit, Vps15, can be found in multiple protein complexes mediating autophagy and endocytic sorting processes. Recent studies have investigated the organismal role of Vps34 by using innovative gene targeting strategies; nonetheless, the role of Vps34 and that of its lipid product, PI3P, in pancreatic physiopathology remain largely unknown. Chronic pancreatitis (CP) is a pathology characterized by progressive tissue destruction, inflammation, and fibrosis of the exocrine pancreas. The pancreas, in spite of being considered a plastic organ, is only capable of limited regeneration. A central regulator of cell regeneration is autophagy and its role in pancreatic pathologies such as type II diabetes and pancreatic cancer is well established; however, its role in CP is just emerging. CP patients present a higher risk for developing pancreatic cancer. Here, we aim to uncover the role of Vps34 in maintaining the differentiation and regenerative potential of exocrine acinar cells through a constant regulation of the autophagic flux. We generated a mouse strain with an inducible Vps34 inactivation in acinar cells, Elas-CreER/Vps34lox/lox (V34 mice) and compared them to control mice. Mice were injected intraperitoneally with tamoxifen (TAM) at the age of 4 weeks to induce gene recombination. Physical examinations, histopathologic analysis, and activity assays were performed at different time points (2, 4, 8, and 16 weeks) to assess the effects of Vps34 inactivation. Under TAM treatment, as compared to control mice, V34 mice presented severely dilated ducts, considerable immune infiltration, moderate to severe fibrosis, and significant fatty replacement of whole lobules of the pancreas (20-35% of pancreatic mass), reminiscent of human CP histology. However, up to 16 weeks, V34 mice did not present yet any remarkable symptoms observed in CP. Our results show that Vps34 inactivation in acinar cells leads to a replacement of pancreatic parenchyma by cells with another differentiated phenotype (adipocytes, duct cells). Since acinar cells are considered as the pancreas alternative progenitor cells, further investigations are needed to understand how Vps34 regulates cell fate in pancreatic pathology, paving the way for novel therapeutic interventions. Citation Format: Fernanda Ramos, Julie Guillermet-Guibert. Uncovering the role of Vps34 in pancreatic autophagy and its relation to chronic pancreatitis, a risk factor for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A05.
Type of Medium:
Online Resource
ISSN:
1541-7786
,
1557-3125
DOI:
10.1158/1557-3125.PI3K-mTOR18-A05
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2098788-2
detail.hit.zdb_id:
2097884-4
SSG:
12
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