Innate immunity pathways and cellular metabolism signalling in pancreatic regeneration and carcinogenesis

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Pancreatic cancer is a devastating disease with a median survival of around 6 months. The molecular mechanisms of pancreatic carcinogenesis are poorly understood and the cell-oforigin is unknown. Recently, it has been shown in genetically engineered mouse models of pancreatic cancer that malignant transformation by endogenous expression of oncogenic Kras can only be achieved in adult animals if concomitant inflammation is present. In experiments preliminary to this proposal, we have defined danger and metabolic signalrelated epithelial proliferation as a key event for overcoming the cell-intrinsic barrier to oncogenic signalling (i.e. via mutated Kras). In this respect, the innate immunity TRIF/TBK1/IRF3/type 1 interferon and the metabolic PPARgamma pathway seem to play important roles in integrating inflammatory and oncogenic signals. We propose as a new concept that inflammation-induced disturbance/de-regulation of these pathways lays the basis for Kras-induced, uncontrolled hyperproliferation and malignant transformation. In this proposal, we thus aim at elucidating the role of these pathways in pancreatic regeneration following inflammatory injury and in early pancreatic carcinogenesis using conditional mouse models and primary, isolated cell systems.