title: Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer.
abstract: Myoferlin is a multiple C2-domain-containing protein that regulates membrane repair, tyrosine kinase receptor function and endocytosis in myoblasts and endothelial cells. Recently it has been reported as overexpressed in several cancers and shown to contribute to proliferation, migration and invasion of cancer cells. We have previously demonstrated that myoferlin regulates epidermal growth factor receptor activity in breast cancer. In the current study, we report a consistent overexpression of myoferlin in triple-negative breast cancer cells (TNBC) over cells originating from other breast cancer subtypes. Using a combination of proteomics, metabolomics and electron microscopy, we demonstrate that myoferlin depletion results in marked alteration of endosomal system and metabolism. Mechanistically, myoferlin depletion caused impaired vesicle traffic that led to a misbalance of saturated/unsaturated fatty acids. This provoked mitochondrial dysfunction in TNBC cells. As a consequence of the major metabolic stress, TNBC cells rapidly triggered AMP activated protein kinase-mediated metabolic reprogramming to glycolysis. This reduced their ability to balance between oxidative phosphorylation and glycolysis, rendering TNBC cells metabolically inflexible, and more sensitive to metabolic drug targeting in vitro. In line with this, our in vivo findings demonstrated a significantly reduced capacity of myoferlin-deficient TNBC cells to metastasise to lungs. The significance of this observation was further supported by clinical data, showing that TNBC patients whose tumors overexpress myoferlin have worst distant metastasis-free and overall survivals. This novel insight into myoferlin function establishes an important link between vesicle traffic, cancer metabolism and progression, offering new diagnostic and therapeutic concepts to develop treatments for TNBC patients.
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: A
authors: A
authors: Blomme
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.|Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors: B
authors: B
authors: Costanza
authors: Center for Interdisciplinary Research on Medicine, CIRM, University of Liège, Liège, Belgium.
authors: P
authors: P
authors: de Tullio
authors: Faculty of Sciences, Laboratory of Cell Biology, University of Liège, Liège, Belgium.
authors: M
authors: M
authors: Thiry
authors: Center for Microscopy and Molecular Imaging, Charleroi, Belgium.|Department of Nuclear Medicine, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
authors: G
authors: G
authors: Van Simaeys
authors: Center for Microscopy and Molecular Imaging, Charleroi, Belgium.|Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Mons, Belgium.
authors: S
authors: S
authors: Boutry
authors: Center for Microscopy and Molecular Imaging, Charleroi, Belgium.
authors: G
authors: G
authors: Doumont
authors: GIGA-Viral Vectors Platform, University of Liège, Liège, Belgium.
authors: E
authors: E
authors: Di Valentin
authors: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors: T
authors: T
authors: Hirano
authors: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors: T
authors: T
authors: Yokobori
authors: BIOTHEQUE, University of Liege, Liege, Belgium.
authors: S
authors: S
authors: Gofflot
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: O
authors: O
authors: Peulen
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: A
authors: A
authors: Bellahcène
authors: Center for Microscopy and Molecular Imaging, Charleroi, Belgium.
authors: F
authors: F
authors: Sherer
authors: Department of Clinical Chemistry, University Hospital, University of Liège, Liège, Belgium.
authors: C
authors: C
authors: Le Goff
authors: Department of Clinical Chemistry, University Hospital, University of Liège, Liège, Belgium.
authors: E
authors: E
authors: Cavalier
authors: Center for Oxygen Research and Development, University of Liège, Liège, Belgium.
authors: A
authors: A
authors: Mouithys-Mickalad
authors: GIGA Cardiovascular Sciences, University of Liège, Liège, Belgium.
authors: F
authors: F
authors: Jouret
authors: Department of Senology, University Hospital, University of Liège, Liège, Belgium.
authors: P G
authors: PG
authors: Cusumano
authors: Department of Senology, University Hospital, University of Liège, Liège, Belgium.
authors: E
authors: E
authors: Lifrange
authors: Center for Microscopy and Molecular Imaging, Charleroi, Belgium.|Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Mons, Belgium.
authors: R N
authors: RN
authors: Muller
authors: Center for Microscopy and Molecular Imaging, Charleroi, Belgium.|Department of Nuclear Medicine, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
authors: S
authors: S
authors: Goldman
authors: Department of Pathology, University Hospital, University of Liège, Liège, Belgium.
authors: P
authors: P
authors: Delvenne
authors: Mass Spectrometry Laboratory, University of Liège, Liège, Belgium.
authors: E
authors: E
authors: De Pauw
authors: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors: M
authors: M
authors: Nishiyama
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: V
authors: V
authors: Castronovo
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.|Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan.|Mass Spectrometry Laboratory, University of Liège, Liège, Belgium.
authors: A
authors: A
authors: Turtoi
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D005260:Female; D006019:Glycolysis; D064593:Heterografts; D006801:Humans; D050356:Lipid Metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009124:Muscle Proteins / Q000096:biosynthesis / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010085:Oxidative Phosphorylation; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D002135:Calcium-Binding Proteins; C415584:MYOF protein, human; D008565:Membrane Proteins; D009124:Muscle Proteins