Expression of Myoferlin in Human and Murine Carcinoma Tumors

Leung, Cleo; Yu, Carol; Lin, Michelle I.; Tognon, Cristina E.; Bernatchez, Pascal

doi:10.1016/j.ajpath.2013.01.041

Cited by 40 publications

(43 citation statements)

References 45 publications

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“…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].…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer, in vivo tumor xenografts lacking myoferlin have been described as smaller, less invasive and less vascularized than their control counterparts [27]. Antitumor effects observed following myoferlin depletion have been attributed to impaired membrane repair/turnover [22], the inability to properly internalize growth factor receptors [21], impaired cancer cell motility [21, 27, 30] and the inability to sustain tumor-associated angiogenesis [20, 28]. However, our study brings forward an additional important role for myoferlin in tumor progression, namely its ability to exert functional impact on exosome biology.…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…A recent report by Leung et al [55] showed that breast and lung cancers express high levels of MYOF and that knockdown with siRNA leads to decreased tumor cell proliferation. In addition, this same group also revealed that loss of MYOF decreased tumor burden in a mouse xenograft model.…”

Section: Discussionmentioning

confidence: 99%

Loss of Myoferlin Redirects Breast Cancer Cell Motility towards Collective Migration

Volakis

Ackerman

et al. 2014

PLoS ONE

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Cell migration plays a central role in the invasion and metastasis of tumors. As cells leave the primary tumor, they undergo an epithelial to mesenchymal transition (EMT) and migrate as single cells. Epithelial tumor cells may also migrate in a highly directional manner as a collective group in some settings. We previously discovered that myoferlin (MYOF) is overexpressed in breast cancer cells and depletion of MYOF results in a mesenchymal to epithelial transition (MET) and reduced invasion through extracellular matrix (ECM). However, the biomechanical mechanisms governing cell motility during MYOF depletion are poorly understood. We first demonstrated that lentivirus-driven shRNA-induced MYOF loss in MDA-MB-231 breast cancer cells (MDA-231MYOF-KD) leads to an epithelial morphology compared to the mesenchymal morphology observed in control (MDA- 231LTVC) and wild-type cells. Knockdown of MYOF led to significant reductions in cell migration velocity and MDA- 231MYOF-KD cells migrated directionally and collectively, while MDA-231LTVC cells exhibited single cell migration. Decreased migration velocity and collective migration were accompanied by significant changes in cell mechanics. MDA-231MYOF-KD cells exhibited a 2-fold decrease in cell stiffness, a 2-fold increase in cell-substrate adhesion and a 1.5-fold decrease in traction force generation. In vivo studies demonstrated that when immunocompromised mice were implanted with MDA- 231MYOF-KD cells, tumors were smaller and demonstrated lower tumor burden. Moreover, MDA- 231MYOF-KD tumors were highly circularized and did not invade locally into the adventia in contrast to MDA- 231LTVC-injected animals. Thus MYOF loss is associated with a change in tumor formation in xenografts and leads to smaller, less invasive tumors. These data indicate that MYOF, a previously unrecognized protein in cancer, is involved in MDA-MB-231 cell migration and contributes to biomechanical alterations. Our results indicate that changes in biomechanical properties following loss of this protein may be an effective way to alter the invasive capacity of cancer cells.

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“…However, recent reports have linked decreased levels of myoferlin to modulating the invasive potential of cancerous cells, where decreased proliferation and migration of myoferlin-depleted cells was seen in vitro . Additionally, myoferlin reduction through siRNA of Lewis Lung Carcinoma (LLC) cells, resulted in reduced membrane repair measured through dye uptake after laser damage (Leung et al, 2013). This data provides evidence myoferlin directs membrane repair and plays a role in efficient proliferation and growth in tumor cells.…”

Section: Membrane Repair and Human Myopathymentioning

confidence: 99%

Plasma Membrane Repair in Health and Disease

Demonbreun

McNally

2016

Current Topics in Membranes

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Since an intact membrane is required for normal cellular homeostasis, membrane repair is essential for cell survival. Human genetic studies, combined with the development of novel animal models and refinement of techniques to study cellular injury, have now uncovered series of repair proteins highly relevant for human health. Many of the deficient repair pathways manifest in skeletal muscle, where defective repair processes result in myopathies or other forms of muscle disease. Dysferlin is a membrane-associated protein implicated in sarcolemmal repair and also linked to other membrane functions including the maintenance of transverse tubules in muscle. MG53, annexins, and Eps15-homology domain (EHD)-containing proteins interact with dysferlin to form a membrane repair complex and similarly have roles in membrane trafficking in muscle. These molecular features of membrane repair are not unique to skeletal muscle, but rather skeletal muscle, due to its high demands, is more dependent on an efficient repair process. Phosphatidylserine and phosphatidylinositol 4, 5 bisphosphate, as well as Ca2+, are central regulators of membrane organization during repair. Given the importance of muscle health in disease and in aging, these pathways are targets to enhance muscle function and recovery from injury.

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Expression of Myoferlin in Human and Murine Carcinoma Tumors

Cited by 40 publications

References 45 publications

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

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

Loss of Myoferlin Redirects Breast Cancer Cell Motility towards Collective Migration

Plasma Membrane Repair in Health and Disease

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