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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the Western world and predicted to be the second one in 2030.1 The initiation, progression, and maintenance of PDAC results from the interplay of genetic events combined with other multiples less well-characterized factors.[2]
We have previously identified a pancreatitis-induced transmembrane protein known as vacuole membrane protein 1 (VMP1), which regulates an inducible form of autophagy.[10,11]
We sought to define the role of VMP1 in the regulation of PDAC initiation using a mechanistic design based on expressing VMP1 in murine pancreatic cells by creating a novel genetically engineered mouse model (GEMM) co-expressing VMP1-DsRed and oncogenic KrasG12D in the exocrine pancreas
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the Western world and predicted to be the second one in 2030.1 The initiation, progression, and maintenance of PDAC results from the interplay of genetic events combined with other multiples less well-characterized factors.[2]. We have previously identified a pancreatitis-induced transmembrane protein known as vacuole membrane protein 1 (VMP1), which regulates an inducible form of autophagy.[10,11] Mechanistically, VMP1 is involved in the phagophore formation by directly binding to beclin1.11 Noteworthy, VMP1 expression is transcriptional induced by oncogenic KRAS via Received 27.12.15; revised 26.5.16; accepted 30.5.16; Edited by GM Fimia a GLI3-p300-dependent mechanism.[12] VMP1 is strongly induced by two complementary PDAC-promoting pathways, namely, pancreatitis and activated KRAS, which further support the hypothesis that this protein may be necessary to initiate neoplastic transformation To test this hypothesis, we developed a novel mice model in which the VMP1 is induced in the pancreas by doxycycline together with activation of the oncogenic KrasG12D. Our findings further underscore the potential utility of inhibiting autophagy to inhibit PDAC growth
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