Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer
Authors: S Boutry
M Nishiyama
P G Cusumano
P Delvenne
A Blomme
V Castronovo
E Cavalier
C Le Goff
E Di Valentin
F Sherer
T Hirano
A Bellahcène
T Yokobori
S Gofflot
M Thiry
A Turtoi
O Peulen
F Jouret
B Costanza
G Van Simaeys
G Doumont
E De Pauw
P de Tullio
S Goldman
A Mouithys-Mickalad
E Lifrange
R N Muller
Journal: Oncogene (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Myoferlin; triple-negative breast cancer; metabolism; vesicle traffic; mitochondrial dysfunction
Affiliations: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium., Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan., Center for Interdisciplinary Research on Medicine, CIRM, University of Liège, Liège, Belgium., Faculty of Sciences, Laboratory of Cell Biology, University of Liège, Liège, Belgium., Center for Microscopy and Molecular Imaging, Charleroi, Belgium., Department of Nuclear Medicine, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium., Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Mons, Belgium., GIGA-Viral Vectors Platform, University of Liège, Liège, Belgium., BIOTHEQUE, University of Liege, Liege, Belgium., Department of Clinical Chemistry, University Hospital, University of Liège, Liège, Belgium., Center for Oxygen Research and Development, University of Liège, Liège, Belgium., GIGA Cardiovascular Sciences, University of Liège, Liège, Belgium., Department of Senology, University Hospital, University of Liège, Liège, Belgium., Department of Pathology, University Hospital, University of Liège, Liège, Belgium., Mass Spectrometry Laboratory, University of Liège, Liège, Belgium.

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. 

Retracted: No

PubPeer comments:
 In figure 5 panel b, the MYOF western-blot (red frame) in MDAMB231 and MDAMB468 are the same. ![file] ,