Exosomes from N-Myc amplified neuroblastoma cells induce migration and confer chemoresistance to non-N-Myc amplified cells: implications of intra-tumour heterogeneity
Exosomes from N-Myc amplified neuroblastoma cells induce migration and confer chemoresistance to non-N-Myc amplified cells: implications of intra-tumour heterogeneity
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DOI：
10.1080/20013078.2019.1597614
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发表时间：
2019-01-01
影响因子：
16
通讯作者：
Mathivanan, Suresh
中科院分区：
文献类型：
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作者：
Fonseka, Pamali;Liem, Michael;Mathivanan, Suresh
神经母细胞瘤占儿童癌症死亡率的15%。癌基因N-Myc扩增是神经母细胞瘤的一个公认的预后不良标志物。虽然N-Myc扩增状态与更高的肿瘤侵袭性和治疗耐药性密切相关，但N-Myc在疾病侵袭性中的作用尚不清楚。外泌体由包括癌细胞在内的许多细胞类型释放，并通过分子货物的转移作为细胞间通信的关键介质。因此，表征N-Myc扩增和非扩增的神经母细胞瘤细胞的外泌体蛋白成分将提高我们对其在神经母细胞瘤进展中的作用的理解。在这项研究中，对不同N-Myc扩增状态的细胞分离的外泌体进行了比较蛋白质组学分析。无标记定量蛋白质组学分析显示，968种蛋白质在神经母细胞瘤细胞释放的外泌体中差异丰富。基于基因本体的分析强调了N-Myc扩增外泌体中参与细胞通信和信号转导的蛋白质的富集。用N-Myc扩增的SK-N-BE2细胞来源的外泌体处理SH-SY5Y细胞，增加了迁移潜力、集落形成能力，并赋予了对阿霉素诱导的细胞凋亡的抗性。N-Myc敲除的SK-N-BE2细胞外泌体的孵育消除了对阿霉素诱导的细胞凋亡的抗性转移。这些发现表明外泌体可能在n - myc驱动的侵袭性神经母细胞瘤和细胞间化疗耐药性的转移中发挥关键作用。
Neuroblastoma accounts for 15% of childhood cancer mortality. Amplification of the oncogene N-Myc is a well-established poor prognostic marker for neuroblastoma. Whilst N-Myc amplification status strongly correlates with higher tumour aggression and resistance to treatment, the role of N-Myc in the aggressiveness of the disease is poorly understood. Exosomes are released by many cell types including cancer cells and are implicated as key mediators in cell-cell communication via the transfer of molecular cargo. Hence, characterising the exosomal protein components from N-Myc amplified and non-amplified neuroblastoma cells will improve our understanding on their role in the progression of neuroblastoma. In this study, a comparative proteomic analysis of exosomes isolated from cells with varying N-Myc amplification status was performed. Label-free quantitative proteomic profiling revealed 968 proteins that are differentially abundant in exosomes released by the neuroblastoma cells. Gene ontology-based analysis highlighted the enrichment of proteins involved in cell communication and signal transduction in N-Myc amplified exosomes. Treatment of SH-SY5Y cells with N-Myc amplified SK-N-BE2 cell-derived exosomes increased the migratory potential, colony forming abilities and conferred resistance to doxorubicin induced apoptosis. Incubation of exosomes from N-Myc knocked down SK-N-BE2 cells abolished the transfer of resistance to doxorubicin induced apoptosis. These findings suggest that exosomes could play a pivotal role in N-Myc-driven aggressive neuroblastoma and transfer of chemoresistance between cells.