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首页> 外文期刊>Oncogene >Tumour exosomes from cells harbouring PTPRZ1|[ndash]|MET fusion contribute to a malignant phenotype and temozolomide chemoresistance in glioblastoma
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Tumour exosomes from cells harbouring PTPRZ1|[ndash]|MET fusion contribute to a malignant phenotype and temozolomide chemoresistance in glioblastoma

机译：携带PTPRZ1 | nb | MET融合细胞的肿瘤外泌体有助于胶质母细胞瘤的恶性表型和替莫唑胺化学耐药性

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Exosomes are carriers of pro-tumorigenic factors that participate in glioblastoma (GBM) progression, and many fusion genes are strong driver mutations in neoplasia and are involved in tumorigenesis. However, the ability of fusion genes to be transduced by exosomes is unknown. We characterized exosomes from GBM cells harbouring and not harbouring PTPRZ1–MET fusion (ZM fusion). We also determined the effect of the exosomes from ZM fusion cells (ZM exosomes) on pro-oncogenic secretions and showed that ZM exosomes are internalized by the recipient cells. In addition, we studied the effect of ZM exosome-mediated intercellular communication in the GBM microenvironment. MET proto-oncogene expression was higher in ZM exosomes. Moreover, phosphorylated MET was detected only in ZM exosomes and not in exosomes released by non-ZM fusion GBM cells. ZM exosomes transferred to non-ZM fusion GBM cells and normal human astrocytes altered gene expression and induced epithelial–mesenchymal transition. The uptake of ZM exosomes also induced an exosome-dependent phenotype defined by GBM cell migration and invasion, neurosphere growth and angiogenesis. In addition, ZM exosomes conferred temozolomide resistance to the GBM cells, and exosome-derived ZM fusion network proteins targeted multiple pro-oncogenic effectors in recipient cells within the GBM microenvironment. Our findings show that exosomes mediate the aggressive character of GBM and demonstrate the role of ZM fusion in the exacerbation of this effect. These findings have possible implications for the foundation of gene fusion-based therapy for managing GBM.
机译：外来体是参与成胶质母细胞瘤（GBM）进展的促肿瘤形成因子的载体，许多融合基因是瘤形成中的强驱动突变，并参与肿瘤发生。但是，融合基因被外来体转导的能力尚不清楚。我们从GBM细胞中隐含和不包含PTPRZ1-MET融合（ZM融合）中鉴定了外泌体。我们还确定了来自ZM融合细胞的外泌体（ZM外泌体）对促癌性分泌的影响，并显示ZM外泌体被受体细胞内化。此外，我们研究了GBM微环境中ZM外来体介导的细胞间通讯的影响。 MET原癌基因在ZM外泌体中表达较高。而且，仅在ZM外泌体中检测到磷酸化的MET，而在非ZM融合GBM细胞释放的外泌体中未检测到。 ZM外泌体转移到非ZM融合的GBM细胞和正常的人类星形胶质细胞改变基因表达并诱导上皮-间质转化。 ZM外泌体的摄取还诱导了外泌体依赖性表型，该表型由GBM细胞迁移和侵袭，神经球生长和血管生成定义。此外，ZM外泌体赋予替莫唑胺对GBM细胞的抗性，而外泌体衍生的ZM融合网络蛋白靶向GBM微环境内受体细胞中的多种致癌效应子。我们的发现表明，外泌体介导了GBM的侵袭性，并证明了ZM融合在这种作用加剧中的作用。这些发现可能为基于基因融合的GBM治疗疗法奠定了基础。

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