Myoferlin controls mitochondrial structure in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness

Pancreatic 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 OXPHOS for survival. Myoferlin, a membrane protein involved in cell fusion was recently shown by our laboratory to be overexpressed in pancreatic cancer. In the present study, we discovered that myoferlin was more expressed in cell lines undergoing oxidative phosphorylation (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 network disorganization. Dynamin-related protein (DRP)-1 phosphorylation led us to suggest mitochondrial fission, reducing cell proliferation, ATP production and inducing autophagy and ROS accumulation. 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. As the mitochondrial function is demonstrated to enhance the cell resistance to the treatment, the metabolic switch forced by myoferlin silencing could open up a new perspective in the development of therapeutic strategies