Pancreatic cancer-initiating cell exosome message transfer into noncancer-initiating cells: the importance of CD44v6 in reprogramming
Pancreatic cancer-initiating cell exosome message transfer into noncancer-initiating cells: the importance of CD44v6 in reprogramming
复制标题
胰腺癌起始细胞外泌体信息转移至非癌症起始细胞：CD44v6 在重编程中的重要性
DOI：
10.1186/s13046-019-1129-8
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发表时间：
2019-03-19
影响因子：
11.3
通讯作者：
Zoeller, Margot
中科院分区：
文献类型：
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作者：
Wang, Zhe;Sun, Hanxue;Zoeller, Margot
背景癌起始细胞（Cancer-initiating cell，CIC）外泌体（exosomes，CIC-TEX）是一种对非CIC基因进行重编程的基因。CIC标志物的信息传递和参与模式存在争议，我们阐述了CD 44 v6和Tspan 8对Non-CIC反应的影响。通过深度测序和功能测定来评估CIC-TEX共培养物诱导的变化。在体内CIC-TEX treatment. ResultsCIC-TEX共培养的CD 44 v6 kd-Non-CIC的深度测序显示显着的mRNA变化的信号，运输，转录和翻译;改变的miRNA影响代谢，信号和转录。CIC-TEX共培养诱导的Tspan 8 kd-非CIC的变化主要依赖于靶向所需的CIC-TEX-Tspan 8。CIC-TEX转移支持细胞凋亡抗性，并在体外和体内显著促进kd非CIC的上皮间质转化、迁移、侵袭和（淋巴）血管生成，深度测序允许个体mRNA和miRNA分配改变的功能。重要的是，CIC-TEX作为枢纽，由CD 44 v6依赖性RTK、GPCR和整合素激活启动，并涉及CD 44 v6辅助的转录和RNA加工。因此，激酶抑制剂阻碍了CIC-TEX促进的肿瘤进展，这是由CIC-TEX binding.ConclusionsThis在体外和体内的CIC-TEX对CD 44 v6 kd和Tspan 8 kd非CIC unravels枢纽CIC-TEX活性的影响的深入报告，突出了CIC-标志物CD 44 v6对信号级联激活，转录，非CIC中的翻译和miRNA加工以及Tspan 8到CIC-TEX的靶向。阻断CIC-TEX结合/摄取和摄取引发的靶细胞活化显著减轻了CIC-TEX对CD 44 v6 kd和Tspan 8 kd非CIC的有害影响。
BackgroundCancer-initiating cell (CIC) exosomes (CIC-TEX) are suggested reprogramming Non-CIC. Mode of message transfer and engagement of CIC-markers being disputed, we elaborated the impact of CD44v6 and Tspan8 on the response of Non-CIC.MethodsNon-metastasizing CD44v6- and Tspan8-knockdown (kd) pancreatic cancer cells served as Non-CIC. CIC-TEX coculture-induced changes were evaluated by deep-sequencing and functional assays. Tumor progression was surveyed during in vivo CIC-TEX treatment.ResultsDeep-sequencing of CIC-TEX-cocultured CD44v6kd-Non-CIC revealed pronounced mRNA changes in signaling, transport, transcription and translation; altered miRNA affected metabolism, signaling and transcription. CIC-TEX coculture-induced changes in Tspan8kd-Non-CIC mostly relied on CIC-TEX-Tspan8 being required for targeting. CIC-TEX transfer supported apoptosis resistance and significantly promoted epithelial mesenchymal transition, migration, invasion and (lymph)angiogenesis of the kd Non-CIC in vitro and in vivo, deep-sequencing allowing individual mRNA and miRNA assignment to altered functions. Importantly, CIC-TEX act as a hub, initiated by CD44v6-dependent RTK, GPCR and integrin activation and involving CD44v6-assisted transcription and RNA processing. Accordingly, a kinase inhibitor hampered CIC-TEX-fostered tumor progression, which was backed by an anti-Tspan8 blockade of CIC-TEX binding.ConclusionsThis in depth report on the in vitro and in vivo impact of CIC-TEX on CD44v6kd and Tspan8kd Non-CIC unravels hub CIC-TEX activity, highlighting a prominent contribution of the CIC-markers CD44v6 to signaling cascade activation, transcription, translation and miRNA processing in Non-CIC and of Tspan8 to CIC-TEX targeting. Blocking CIC-TEX binding/uptake and uptake-initiated target cell activation significantly mitigated the deleterious CIC-TEX impact on CD44v6kd and Tspan8kd Non-CIC.