Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer - Université de Montpellier Accéder directement au contenu
Article Dans Une Revue Oncogene Année : 2017

Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer

A Blomme
  • Fonction : Auteur
B Costanza
  • Fonction : Auteur
M. Thiry
  • Fonction : Auteur
T. Hirano
  • Fonction : Auteur
T Yokobori
  • Fonction : Auteur
O Peulen
  • Fonction : Auteur
F Jouret
  • Fonction : Auteur
M Nishiyama
  • Fonction : Auteur

Résumé

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.
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Dates et versions

hal-02444019 , version 1 (17-01-2020)

Identifiants

Citer

A Blomme, B Costanza, P de Tullio, M. Thiry, G van Simaeys, et al.. Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer. Oncogene, 2017, 36 (15), pp.2116-2130. ⟨10.1038/onc.2016.369⟩. ⟨hal-02444019⟩
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