The Pancreatitis-Associated Protein VMP1, a Key Regulator of Inducible Autophagy, Promotes KrasG12D-Mediated Pancreatic Cancer Initiation

LONCLE C; MOLEJON MI; LAC S; TELLECHEA JI; LOMBERK G; GRAMATICA L; FERNANDEZ-ZAPICO, ME; DUSETTI N; URRUTIA R; IOVANNA JL

Cell Death and Disease

NATURE PUBLISHING GROUP

Año: 2016

Both clinical and experimental evidence have firmly established that chronic pancreatitis, inparticular in the context of Kras oncogenic mutations, predisposes to pancreatic ductaladenocarcinoma (PDAC). However, the repertoire of molecular mediators of pancreatitis involved inKras-mediated initiation of pancreatic carcinogenesis remains to be fully defined. In this study wedemonstrate a novel role for VMP1, a pancreatitis-associated protein critical for inducible autophagy,in the regulation of Kras-induced PDAC initiation. Using a newly developed genetically engineeredmodel, we demonstrate that VMP1 increases the ability of Kras to give rise to preneoplastic lesions,PanINs. This promoting effect of VMP1 on PanIN formation is due, at least in part, by an increase incell proliferation combined with a decrease in apoptosis. Using chloroquine, an inhibitor ofautophagy, we show that this drug antagonizes the effect of VMP1 on PanIN formation. Thus, weconclude that VMP1-mediated autophagy cooperate with Kras to promote PDAC initiation. Thesefindings are of significant medical relevance, molecules targeting autophagy are currently beingtested along chemotherapeutic agents to treat PDAC and other tumors in human trials.