Autophagy Induced during Pancreatitis PromotesKRAS-Dependent Transformation in the Pancreas.
Pancreatitis is an inflammatory disease that both facilitates and accelerates the transformation of pancreatic cells upon activation of theKRASoncogene. Autophagy is proposed to be one of the cellular mechanisms contributing to pancreatic carcinogenesis, especially during initial stages in which theKRASoncogene appears to play a key role. Autophagy is also strongly induced during pancreatitis by the overexpression ofVMP1. We recently developed a genetically engineered mouse model in which the VMP1 protein is induced simultaneously with the activation of the oncogeneKrasG12Dspecifically in the pancreas, by the addition of doxycycline to a water drink. Using this sophisticated animal model, we can affirm that pancreatic autophagy, induced during pancreatitis by the overexpression ofVMP1, promotes the development of precancerous lesions when induced by the mutatedKRAS. In addition, the treatment of these mice with chloroquine, an inhibitor of autophagic flux, reverses the effects of VMP1 in pancreatic cancer induced by theKRASoncogene. Overall, these results bear both mechanistic and biomedical relevance for further understanding and potentially targeting pathways that are critical for initiating pancreatic carcinogenesis, particularly if associated with pancreatitis.
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université et Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy , Marseille , France.
Juan L
JL
Iovanna
KRAS; VMP1; autophagy; chloroquine; pancreatic cancer; pancreatitis