Tumour exosomes from cells harbouring PTPRZ1-MET fusion contribute to a malignant phenotype and temozolomide chemoresistance in glioblastoma.
Tumour exosomes from cells harbouring PTPRZ1-MET fusion contribute to a malignant phenotype and temozolomide chemoresistance in glioblastoma.
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来自含有 PTPRZ1-MET 融合的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疗耐药性
DOI：
10.1038/onc.2017.134
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发表时间：
2017-09-21
期刊：
影响因子：
8
通讯作者：
You YP
中科院分区：
文献类型：
--
作者：
Zeng AL;Yan W;Liu YW;Wang Z;Hu Q;Nie E;Zhou X;Li R;Wang XF;Jiang T;You YP
外泌体是参与胶质母细胞瘤（GBM）进展的促瘤因子的载体，许多融合基因在瘤变中是强驱动突变并参与肿瘤发生。然而，融合基因被外泌体转导的能力尚不清楚。我们鉴定了来自GBM细胞的外泌体携带和不携带PTPRZ1-MET融合（ZM融合）。我们还确定了来自ZM融合细胞的外泌体（ZM外泌体）对促癌分泌物的影响，并表明ZM外泌体被受体细胞内化。此外，我们还研究了ZM外泌体介导的细胞间通讯在GBM微环境中的作用。MET原癌基因在ZM外泌体中的表达较高。此外，仅在ZM外泌体中检测到磷酸化MET，而在非ZM融合的GBM细胞释放的外泌体中未检测到磷酸化MET。ZM外泌体转移到非ZM融合的GBM细胞和正常人类星形胶质细胞中，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由GBM细胞迁移和侵袭、神经球生长和血管生成所定义的外泌体依赖表型。此外，ZM外泌体赋予了对GBM细胞的替莫唑胺耐药性，外泌体衍生的ZM融合网络蛋白靶向GBM微环境中受体细胞中的多种促癌效应物。我们的研究结果表明，外泌体介导了GBM的侵袭性，并证明了ZM融合在加剧这种影响中的作用。这些发现可能对基因融合治疗GBM的基础产生影响。
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.
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