Myoferlin is a novel exosomal protein and functional regulator of cancer-derived exosomes

Abstract

Exosomes are communication mediators participating in the intercellular exchange of proteins, metabolites and nucleic acids. Recent studies have demonstrated that exosomes are characterized by a unique proteomic composition that is distinct from the cellular one. The mechanisms responsible for determining the proteome content of the exosomes remain however obscure. In the current study we employ ultrastructural approach to validate a novel exosomal protein myoferlin. This is a multiple C2-domain containing protein, known for its conserved physiological function in endocytosis and vesicle fusion biology. Emerging studies demonstrate that myoferlin is frequently overexpressed in cancer, where it promotes cancer cell migration and invasion. Our data expand these findings by showing that myoferlin is a general component of cancer cell derived exosomes from different breast and pancreatic cancer cell lines. Using proteomic analysis, we demonstrate for the first time that myoferlin depletion in cancer cells leads to a significantly modulated exosomal protein load. Such myoferlin-depleted exosomes were also functionally deficient as shown by their reduced capacity to transfer nucleic acids to human endothelial cells (HUVEC). Beyond this, myoferlin-depleted cancer exosomes also had a significantly reduced ability to induce migration and proliferation of HUVEC. The present study highlights myoferlin as a new functional player in exosome biology, calling for novel strategies to target this emerging oncogene in human cancer.

Myoferlin, a multifunctional protein in normal cells, has novel and key roles in various cancers

“…The latest research shows that myoferlin regulates cancer-derived exosomes and functions as a new player in exosome biology. 41 As mentioned above, myoferlin impacts tumour-associated angiogenesis by affecting VEGFA secretion and EGFR activity. 36,66 These findings suggest that myoferlin induces the malignant phenotype of cancers by altering the tumour microenvironment.…”

“…Myoferlin is involved in the proliferation, 34 invasion and migration 35 of cancer cells via different mechanisms, mainly including promoting angiogenesis, 36 vasculogenic mimicry, 37 energy metabolism reprogramming, 38,39 epithelial-mesenchymal transition (EMT) 40 and affecting exosomes. 41 Clinically, myoferlin levels correlate with histologic grade and prognosis in several types of cancers. Of note, the functions and mechanisms of myoferlin in cancers have not been thoroughly revealed to date.…”

The cancer exosomes: Clinical implications, applications and challenges

“…sequenced exosomal circular RNA (circRNA) and assumed that circPTGR1 in exosomes regulated higher metastatic hepatocellular carcinoma (HCC) cells to confer metastasis potential on lower or no metastatic potential, resulting in increasing their migratory and invasive abilities (Table ). Besides, novel function exosomal protein Myoferlin was also validated to facilitate tumor metastasis . Exosomal new functional ingredients call for novel strategies to further reveal this emerging metastatic correlation in human cancer.…”

Examining the Paracrine Effects of Exosomes in Cardiovascular Disease and Repair

“…Exosomes contain lipids, proteins, RNAs, and microRNAs (miRs) . The composition of exosomes not only differs from microvesicles and apoptotic bodies but also varies depending on cell type of origin, disease status, or stimuli during formation . The exosome composition and internal cargo determine the outcome of the intercellular communication .…”

“…5,6 The composition of exosomes not only differs from microvesicles and apoptotic bodies 4 but also varies depending on cell type of origin, disease status, or stimuli during formation. [42][43][44][45] The exosome composition and internal cargo determine the outcome of the intercellular communication. 46 The field of exosome research is continuously expanding.…”