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.

Innovative methods for biomarker discovery in the evaluation and development of cancer precision therapies

“…In the same line, our group has identified myoferlin, a novel exosomal protein, as a potential prognostic marker in breast cancer and pancreatic cancer [111][112][113][114]. We have demonstrated that overexpression of myoferlin in triple negative breast cancer (TNBC) is a negative prognostic factor associated with worse overall survival (OS) and metastatic disease [112]. Our findings in pancreatic cancer also reveal a correlation between myoferlin overexpression and a poor clinical outcome [114].…”

“…Investigators have demonstrated that CD63+ exosomes are present at a higher level in malignant cells compared to normal cells [107,110]. In the same line, our group has identified myoferlin, a novel exosomal protein, as a potential prognostic marker in breast cancer and pancreatic cancer [111][112][113][114]. We have demonstrated that overexpression of myoferlin in triple negative breast cancer (TNBC) is a negative prognostic factor associated with worse overall survival (OS) and metastatic disease [112].…”

Enzymatic cleavage of myoferlin releases a dual C2-domain module linked to ERK signalling

“…Our ongoing studies will explore the consequence of myoferlin over-expression on MAPK/ERK signalling pathways in a transgenic mouse model, to better elucidate the functional consequences of myoferlin cleavage and its potential relationship to growth factor receptor signalling and the metastatic properties of cancer cells. Enzymatic cleavage of myoferlin may explain detection of myoferlin as a 240/170 kDa N-terminal doublet band in tumour samples and cancer cell lines in recent reports describing a role for myoferlin in tumorigenesis and cancer cell metastasis [16,28–30], potentially illuminating a functional adaptation of myoferlin relevant to cellular signalling and oncogenesis.…”

“…Our interest in myoferlin was piqued by reports showing myoferlin as a doublet band in western blots when detected with N-terminal epitope specific antibodies [16,28–30]. This was reminiscent of the N-terminal calpain-cleavage fragment we reported for dysferlin [26,27].…”

Down‐regulating Myoferlin inhibits the vasculogenic mimicry of melanoma via decreasing MMP‐2 and inducing mesenchymal‐to‐epithelial transition

“…VM v 2 P value Yes (14) No ( results, the expression of MMP-2 decreased more than 40% in MYOF down-regulated cells (Fig. 3C), which correlates with the decreased mRNA levels detected by RT-PCR (Fig.…”