Project Summary Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with a 5-year survival rate of only 6% and is expected to become the second most common cause of cancer-related death in the United States by 2030. Genetic factors are thought to be responsible for only 10 % of all PDAC cases. Several risk factors greatly increase the likelihood that premalignant lesions will progress to PDAC, including tobacco smoking, obesity, alcohol consumption and chronic pancreatitis. Recent epidemiological studies have shown a relationship between high fructose intake and pancreatic cancer. Main sources of fructose in our diet are cane sugar (sucrose) and high-fructose corn syrup, a common sweetener that has primarily replaced sucrose. The specific mechanism whereby high fructose intake may affect PDAC development remains speculative. We fed mice expressing oncogenic Kras high fructose diet, which resulted in increased number of preneoplastic lesions, tumor incidence, inflammation and fibrosis and induced expression of enzymes of glycolysis and the pentose phosphate pathway (PPP), both of which show increased rates in cancer. Interestingly, the levels of signaling adaptor p62 that is often up regulated in cancer were also increased in pancreata of these mice comparing to their littermates fed isocaloric control diet rich in cornstarch. p62 is a key driver of malignant conversion, whose accumulation promotes tumorigenesis in several tumor types such as hepatoma, non- small-cell-lung cancer, breast cancer and PDAC. In addition to binding poly-ubiquitinated protein aggregates and targeting them for degradation by autophagy, p62 is a signaling adaptor that promotes activation of NF-?B and NRF2 transcription factors and mTORC1. Given that both, NRF2 and mTOR pathways were shown to control pancreatic intraepithelial neoplasia1 (PanIN1) to PDAC progression and to redirect glucose into anabolic pathways glycolysis and PPP, we postulated that high fructose intake may stimulate PanIN1 to PDAC progression via p62-NRF2 and p62-mTOR cascades. The aim of this project is to elucidate the mechanisms that link increased fructose consumption to pancreatic cancer and the role of p62 in this process. In summary, this study should provide novel insights into high fructose intake-mediated PDAC development and help create awareness about the health risks of high fructose intake ultimately resulting in decreased PDAC incidence and mortality.