Myoferlin plays a key role in VEGFA secretion and impacts tumor‐associated angiogenesis in human pancreas cancer

Abstract

Pancreatic ductal adenocarcinoma is one of the most deadly forms of cancers with no satisfactory treatment to date. Recent studies have identified myoferlin, a ferlin family member, in human pancreas adenocarcinoma where its expression was associated to a bad prognosis. However, the function of myoferlin in pancreas adenocarcinoma has not been reported. In other cell types, myoferlin is involved in several key plasma membrane processes such as fusion, repair, endocytosis and tyrosine kinase receptor activity. In this study, we showed that myoferlin silencing in BxPC-3 human pancreatic cancer cells resulted in the inhibition of cell proliferation in vitro and in a significant reduction of the tumor volume in chick chorioallantoic membrane assay. In addition to be smaller, the tumors formed by the myoferlin-silenced cells showed a marked absence of functional blood vessels. We further demonstrated that this effect was due, at least in part, to an inhibition of VEGFA secretion by BxPC-3 myoferlin-silenced cells. Using immunofluorescence and electron microscopy, we linked the decreased VEGFA secretion to an impairment of VEGFA exocytosis. The clinical relevance of our results was further strengthened by a significant correlation between myoferlin expression in a series of human pancreatic malignant lesions and their angiogenic status evaluated by the determination of the blood vessel density.

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

“…A paucity of studies demonstrates that exosomes are mediators that facilitate intercellular exchange of biomolecules, assuming an important role in cell-to-cell communication [29]. In the current study we focused on myoferlin, a membrane associated protein, which has recently been demonstrated to be pro-oncogenic in several types of cancer [21, 22, 26–28, 30]. In breast cancer, in vivo tumor xenografts lacking myoferlin have been described as smaller, less invasive and less vascularized than their control counterparts [27].…”

“…Further studies performed in endothelial cells demonstrated that myoferlin is important for membrane repair and endocytosis [17] as well as receptor-mediated angiogenesis [18–21]. In cancer, overexpression of the protein has been reported in breast, lung, and pancreatic tumors [22–25], where it is associated with increased tumorigenic potential and angiogenesis [21, 26–28]. Mechanistically, myoferlin has been shown to control both endocytosis (EGFR, VEGFR2, IGFR and Tie-2) and exocytosis (VEGF) of several key molecules [18–21, 28].…”

“…In cancer, overexpression of the protein has been reported in breast, lung, and pancreatic tumors [22–25], where it is associated with increased tumorigenic potential and angiogenesis [21, 26–28]. Mechanistically, myoferlin has been shown to control both endocytosis (EGFR, VEGFR2, IGFR and Tie-2) and exocytosis (VEGF) of several key molecules [18–21, 28]. Inspired by myoferlins' role in cell membrane biology, we hypothesized that myoferlin could be essential to exosomes in regulating their maturation, secretion or internalization.…”

Development of bioluminescent chick chorioallantoic membrane (CAM) models from primary pancreatic cancer cells: A platform for drug testing

“…However, previously it has been shown that the long-term maintenance in culture of PDAC cell lines, such as BxPC-3, CFPAC-1 and PANC-1 cells 33,34 , resulted in distinct and irreversible loss of crucial genetic and biologic properties. This included the occurrence of distinct stem cell populations and complex genomic aberrations, affecting critical signaling pathways 35,36 .…”

In-depth proteomic profiling of the uveal melanoma secretome

“…In particular, C1s/C1r are reported to degrade collagen and are involved in activation of CUB domain containing proteins that regulate many aspects of cancer progression and metastasis [44]. SNAP23 is a key regulator of the membrane-membrane fusion events required for intracellular membrane traffic and has been reported to traffic matrix metalloproteases during degradation of ECM substrates, thus enabling cellular invasion [45], whilst myoferlin is involved in increased tumor associated angiogenesis [46, 47]. The differential expression of exosomal proteins both between HR and LR UM, and also between all UM and NCM may suggest basic differences in exosome biogenesis and trafficking.…”