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Our long-term goals are to identify how metabolic rewiring impacts the epigenome to guide cell fate decisions or facilitate cancer initiation. We intend to define the contribution of acetyl-CoA generation to metabolic and epigenetic remodeling in a number of different contexts: 1) Dissect the contribution of mitochondrial dynamics to epigenetic reprogramming in cancer The role of mitochondria for the generation of acetyl-CoA, and the downstream effects on chromatin landscapes remain unknown. We study how changes in mitochondrial shape or localization impact acetyl-CoA flux and whether mitochondrial dynamics dictate epigenetic state in cancer. 2) Role of mitochondrial cristae remodeling in pancreatic cancer progression Mitochondria are functioning in cancer cells, but their activity is profoundly rewired. The underlying mechanism is not clear. We found that mitochondrial ultrastructure is altered early in pancreatic carcinogenesis. We are studying the impact of mitochondrial remodeling for carcinogenesis using mouse models of impaired cristae biogenesis. 3) Determinants of citrate cataplerosis Acetyl-CoA is generated by mitochondrial-derived citrate. The conversion is mediated by ACLY, which has been shown to be important for cell differentiation and stemness, both in physiological and pathological conditions. However, what determines efflux of citrate (cataplerosis) from mitochondria is not clear. Using histone acetylation and cell de-differentiation as read-outs, we are interrogating cellular metabolites that might regulate the fate of mitochondrial citrate. 4) Molecular memory of inflammation Inflammation increases the risk of pancreatic cancer onset, even several years after complete recovery. Combining single nucleus RNA/ATAC sequencing, mouse modeling and epigenomic profiling we are interrogating the metabolic determinants of pancreatic cancer susceptibility after recovery from acute inflammation. 5) Dietary contribution to pancreatic carcinogenesis Several unhealthy lifestyles are associated with increased pancreatic cancer risk, but the role of diet is still somehow debated. We are examining the role of dietary fructose to pancreatic cancer predisposition and interrogating possible mechanisms, with a focus on fructose-derived acetate and protein acetylation. 6) Cholesterol homeostasis and signaling in pancreatitis and pancreatic cancer progressions De novo sterol synthesis is elevated in pancreatic cancer cells. Moreover, its cholesterol homeostasis is deregulated in tumor-initiating pancreatitis. We found that cholesterol supplementation promotes metaplasia of pancreatic acinar cells. We are currently investigating how dysregulation of cholesterol availability activates intracellular signaling and supports extracellular inflammation. 7) Metabolic-dependent histone acetylation in B cell pathophysiology Histone acetylation is enhanced in B cell germinal centers and derived leukemias. This is amenable to therapeutic strategies, but the contribution of metabolism and its role in modifying therapy response is unclear. In collaboration with the groups of F. Piazza and G. Semenzato, and leveraging our orthogonal expertise, we are studying the role of ACLY in B cell differentiation and proliferation in health and disease.