Myoferlin Is a Key Regulator of EGFR Activity in Breast Cancer

Turtoï, Andrei; Blomme, Arnaud; Bellahcène, Akeila; Gilles, Christine; Hennequière, Vincent; Peixoto, Paul; Bianchi, Elettra; Noël, Agnès; Pauw, Edwin De; Lifrange, Eric; Delvenne, Philippe; Castronovo, Vincenzo

doi:10.1158/0008-5472.can-13-1142

Cited by 66 publications

(109 citation statements)

References 36 publications

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“…Our laboratory recently described myoferlin as a key regulator of EGFR activity in breast cancer. 16 In endothelial cells, it was found to regulate VEGFR2 biological activity through preventing its polyubiquitination and its subsequent degradation by the proteasome. 4 In the same cell type the expression of angiopoietin-1 receptor (TIE-2) seemed to be myoferlin-dependent.…”

Section: Discussionmentioning

confidence: 99%

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

Fahmy

Gonzalez

Arafa

et al. 2015

Intl Journal of Cancer

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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.

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Section: Discussionmentioning

confidence: 99%

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

Fahmy

Gonzalez

Arafa

et al. 2015

Intl Journal of Cancer

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“…5E). Likewise, myoferlin (MYOF), a gene linked to breast cancer progression (36) and metastasis of pancreatic carcinoma (37), was downregulated in Colo-205 cells (Fig. 5B and Supplementary Fig.…”

Section: B-rafmentioning

confidence: 97%

B-Raf Inhibitors Induce Epithelial Differentiation inBRAF-Mutant Colorectal Cancer Cells

et al. 2015

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BRAF mutations are associated with aggressive, less-differentiated and therapy-resistant colorectal carcinoma. However, the underlying mechanisms for these correlations remain unknown. To understand how oncogenic B-Raf contributes to carcinogenesis, in particular to aspects other than cellular proliferation and survival, we generated three isogenic human colorectal carcinoma cell line models in which we can dynamically modulate the expression of the B-Raf V600E oncoprotein. Doxycyclin-inducible knockdown of endogenous B-Raf V600E decreases cellular motility and invasion in conventional and three-dimensional (3D) culture, whereas it promotes cell-cell contacts and induces various hallmarks of differentiated epithelia. Importantly, all these effects are recapitulated by B-Raf (PLX4720, vemurafenib, and dabrafenib) or MEK inhibitors (trametinib). Surprisingly, loss of B-Raf V600E in HT29 xenografts does not only stall tumor growth, but also induces glandular structures with marked expression of CDX2, a tumor-suppressor and master transcription factor of intestinal differentiation. By performing the first transcriptome profiles of PLX4720-treated 3D cultures of HT29 and Colo-205 cells, we identify several upregulated genes linked to epithelial differentiation and effector functions, such as claudin-1, a Cdx-2 target gene encoding a critical tight junction component. Thereby, we provide a mechanism for the clinically observed correlation between mutant BRAF and the loss of Cdx-2 and claudin-1. PLX4720 also suppressed several metastasis-associated transcripts that have not been implicated as targets, effectors or potential biomarkers of oncogenic B-Raf signaling so far. Together, we identify a novel facet of clinically applied B-Raf or MEK inhibitors by showing that they promote cellular adhesion and differentiation of colorectal carcinoma cells.

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“…It had been first identified in muscle cells, where it contributes to cell/cell fusion and muscle regeneration [15, 16]. 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].…”

Section: Introductionmentioning

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%

“…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.…”

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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Myoferlin Is a Key Regulator of EGFR Activity in Breast Cancer

Cited by 66 publications

References 36 publications

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

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

B-Raf Inhibitors Induce Epithelial Differentiation inBRAF-Mutant Colorectal Cancer Cells

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

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