Exploring the Role of Mitochondrial Fission in Pancreatic Tumorigenesis



 DESCRIPTION (provided by applicant): Over 90% of pancreatic cancers harbor a mutation in the Ras gene, yet identifying drugs that target the mutant Ras protein have proven difficult. Therefore, it is critical that we understand the biochemical and physiological changes elicited by mutant Ras so that we can identify drug targets more amenable to pharmacological intervention. To that end, Ras-driven pancreatic tumors are characterized by changes in mitochondrial function. The mitochondria are organelles present within the cell that are responsible for generating energy and providing the building blocks required for cellular proliferation. We have uncovered a novel link between the activity of Ras proteins and the cellular machinery that controls the fusion and fission of the mitochondria. Recent research indicates that the regulation mitochondrial fusion and fission greatly impacts mitochondrial function. We hypothesize that altering the balance of mitochondrial fusion and fission is required for mutant Ras to promote excess proliferation and that the mitochondrial fusion and fission machinery might represent an attractive drug target for pancreatic cancer. In aim 1, our goal is to elucidate the physiological consequences of Ras- induced mitochondrial fission in a series of patient-derived pancreatic cancer cell lines. In aims two and three, our goal is to use two complementary and physiologically relevant mouse models of pancreatic ductal adenocarcinoma to test the requirement of mitochondrial fission for pancreatic tumor growth and explore whether the mitochondrial fission machinery might be a viable drug target. Completion of these aims will give us a better understanding of the important role mitochondrial function plays in pancreatic cancer and allow us to identify novel targets for therapeutic intervention.