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

• Published in: Oncogene Vol. 37; no. 32; pp. 4398 - 4412
• Main Authors: Rademaker, Gilles, Hennequière, Vincent, Brohée, Laura, Nokin, Marie-Julie, Lovinfosse, Pierre, Durieux, Florence, Gofflot, Stéphanie, Bellier, Justine, Costanza, Brunella, Herfs, Michael, Peiffer, Raphael, Bettendorff, Lucien, Deroanne, Christophe, Thiry, Marc, Delvenne, Philippe, Hustinx, Roland, Bellahcène, Akeila, Castronovo, Vincent, Peulen, Olivier
• Format: Journal Article Web Resource
• Language: English
• Published: London Nature Publishing Group UK 01-08-2018; Nature Publishing Group
• Subjects: 101/28; 13/109; 13/51; 14/1; 14/34; 631/67/1504/1713; 631/67/2327; Adenocarcinoma; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenosine Triphosphate - metabolism; Apoptosis; Autophagy; Autophagy - physiology; Biochemistry, biophysics & molecular biology; Biochimie, biophysique & biologie moléculaire; Calcium-Binding Proteins - metabolism; Cancer; Cancer treatment; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Care and treatment; Cell Biology; Cell Line, Tumor; Cell membranes; Cell proliferation; Cell Proliferation - physiology; Cellular proteins; Chemotherapy; Death; Deoxyglucose; Development and progression; Diagnostic imaging; Energy metabolism; Energy Metabolism - physiology; Fitness; Gastroenterology & hepatology; Gastroentérologie & hépatologie; Gene expression; Gene Expression Regulation, Neoplastic - physiology; Genetic aspects; Glycolysis; Glycolysis - physiology; Health aspects; Human Genetics; Human health sciences; Humans; Internal Medicine; Life sciences; Medicine; Medicine & Public Health; Membrane Proteins - metabolism; Metabolism; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Muscle Proteins - metabolism; Neurophysiology; Oncologie; Oncology; Oxidative Phosphorylation; pancreas; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phagocytosis; Phenotypes; Phosphorylation; Positron emission tomography; RNA; RNA, Small Interfering - metabolism; Sciences de la santé humaine; Sciences du vivant; siRNA; Therapeutic applications; Therapeutics; Tomography; Tumor cell lines; Tumors
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-018-0287-z

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by
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F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism.