PO-242 Myoferlin controls mitochondrial structure and metabolism in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness

Abstract

IntroductionPancreatic ductal adenocarcinoma (pdac) is the most common type of pancreatic cancer, and the third leading cause of cancer related death. therapeutic options remain very limited and are still based on classical chemotherapies. cell fraction can survive to the chemotherapy and is responsible for tumor relapse. it appears that these cells rely on oxydative phosphorylation (oxphos) for survival.Myoferlin, a membrane protein involved in cell fusion was recently shown by our laboratory to be overexpressed in pancreatic cancer.Material and methodsWe used pancreatic cancer cell lines depleted in myoferlin to assess mitochondrial function with an extracellular flux analyser. pancreas cancer samples from the institutional biobank with matched pet scan data were used to correlate myoferlin abundance and glycolysis.results and discussionsin the present study, we discovered that myoferlin was more expressed in cell lines undergoing (oxphos) than in glycolytic cell lines. in the former cell lines, we showed that myoferlin silencing reduced oxphos activity and forced cells to switch to glycolysis. the decrease in oxphos activity is associated with mitochondrial condensation and network disorganization. an increase of dynamin-related protein (drp)-1 phosphorylation in myoferlin-depleted cells led us to suggest mitochondrial fission, reducing cell proliferation, atp production and inducing autophagy and ros accumulation. electron microscopy observation revealed mitophagy, suggesting mitochondrial alterations.To confirm the clinical importance of myoferlin in pdac, we showed that low myoferlin expression was significantly correlated to high overall survival. myoferlin staining of pdac sections was negatively correlated with several 18fdg pet indices indicating that glycolytic lesions had less myoferlin. these observations are fully in accordance with our in vitro data.conclusionas the mitochondrial function was associated with cell chemoresistance, the metabolic switch induced by myoferlin silencing could open up a new perspective in the development of therapeutic strategies. among them, targeting functional domains (c2, dysf, …) of myoferlin should be a priority.