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

Oncogene volume 36, pages 2116–2130 (2017)Cite this article

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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.

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Acknowledgements

We acknowledge the experimental support of Dr Chantal Humblet and Mrs Alice Marquet (GIGA-histology platform, ULg), Dr Sandra Ormenese (GIGA-imaging platform, ULg), Mr Vincent Hennequière and Mrs Naima Maloujahmoum (Metastasis Research Laboratory) for experimental support. We are also thankful to the institutional Biobank of the University Hospital Liege for providing patient material. Mr Mathieu Roch (CMMI) is thanked for his help in tumor volume measurements on MR images. We are grateful to Mrs Marie-Aline Laute and Mr Nicolas Passon, the Cyclotron team (Erasme Hospital, Brussels, Belgium) and Dr. Bolag Altan (Gunma University) for technical assistance. The results shown in this work are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. This work was supported with grants from the University of Liège (Concerted Research Action Program (IDEA project)), National Fund for Scientific Research (FNRS), Fonds Erasme, Convention de Recherche Association Vinçotte Nuclear—AVN and Gunma University (GIAR Research Program for Omics-Based Medical Science). Andrei Turtoi and Arnaud Blomme are post-doctoral research fellows (FNRS/Televie), Akeila Bellahcène and Pascal de Tullio are senior research associates (FNRS). The Center for Microscopy and Molecular Imaging (CMMI) as well as Gilles Doumont are supported by the European Regional Development Fund and Wallonia (FEDER). No funding bodies had any role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium

    A Blomme, B Costanza, O Peulen, A Bellahcène, V Castronovo & A Turtoi

  2. Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan

    B Costanza, T Yokobori, M Nishiyama & A Turtoi

  3. Center for Interdisciplinary Research on Medicine, CIRM, University of Liège, Liège, Belgium

    P de Tullio

  4. Faculty of Sciences, Laboratory of Cell Biology, University of Liège, Liège, Belgium

    M Thiry

  5. Center for Microscopy and Molecular Imaging, Charleroi, Belgium

    G Van Simaeys, S Boutry, G Doumont, F Sherer, R N Muller & S Goldman

  6. Department of Nuclear Medicine, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium

    G Van Simaeys & S Goldman

  7. Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Mons, Belgium

    S Boutry & R N Muller

  8. GIGA-Viral Vectors Platform, University of Liège, Liège, Belgium

    E Di Valentin

  9. Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan

    T Hirano

  10. BIOTHEQUE, University of Liege, Liege, Belgium

    S Gofflot

  11. Department of Clinical Chemistry, University Hospital, University of Liège, Liège, Belgium

    C Le Goff & E Cavalier

  12. Center for Oxygen Research and Development, University of Liège, Liège, Belgium

    A Mouithys-Mickalad

  13. GIGA Cardiovascular Sciences, University of Liège, Liège, Belgium

    F Jouret

  14. Department of Senology, University Hospital, University of Liège, Liège, Belgium

    P G Cusumano & E Lifrange

  15. Department of Pathology, University Hospital, University of Liège, Liège, Belgium

    P Delvenne

  16. Mass Spectrometry Laboratory, University of Liège, Liège, Belgium

    E De Pauw & A Turtoi

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Correspondence to A Turtoi.

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Blomme, A., Costanza, B., de Tullio, P. et al. Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer. Oncogene 36, 2116–2130 (2017). https://doi.org/10.1038/onc.2016.369

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