Extracellular vesicles containing oncogenic mutant β-catenin activate Wnt signalling pathway in the recipient cells
Extracellular vesicles containing oncogenic mutant β-catenin activate Wnt signalling pathway in the recipient cells
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DOI：
10.1080/20013078.2019.1690217
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发表时间：
2019-12-01
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：
Kalra, Hina;Gangoda, Lahiru;Mathivanan, Suresh
β-连环蛋白的突变，特别是在其降解的关键残基上的突变，使其具有组成性活性。在这里，我们表明，突变的β-连环蛋白可以通过细胞外囊泡（EV）运输，并激活受体细胞中的Wnt信号通路。一项综合蛋白基因组学分析鉴定了结直肠癌（CRC）细胞分泌的EV中存在突变的β-连环蛋白。后续实验证实，从LIM 1215 CRC细胞释放的EV刺激具有野生型β-连环蛋白的受体细胞中的Wnt信号通路。基于SILAC的定量蛋白质组学分析证实了突变的β-连环蛋白转移到受体细胞的细胞核中。DiR标记的EV在植入RKO CRC细胞的小鼠中的体内追踪揭示了其生物分布，证实了肿瘤细胞中Wnt信号传导途径的激活并增加了肿瘤负荷。总的来说，这项研究首次揭示了EV可以将突变的β-连环蛋白转移到受体细胞并促进癌症进展。
Mutations in beta-catenin, especially at the residues critical for its degradation, render it constitutively active. Here, we show that mutant beta-catenin can be transported via extracellular vesicles (EVs) and activate Wnt signalling pathway in the recipient cells. An integrative proteogenomic analysis identified the presence of mutated beta-catenin in EVs secreted by colorectal cancer (CRC) cells. Follow-up experiments established that EVs released from LIM1215 CRC cells stimulated Wnt signalling pathway in the recipient cells with wild-type beta-catenin. SILAC-based quantitative proteomics analysis confirmed the transfer of mutant beta-catenin to the nucleus of the recipient cells. In vivo tracking of DiR-labelled EVs in mouse implanted with RKO CRC cells revealed its bio-distribution, confirmed the activation of Wnt signalling pathway in tumour cells and increased the tumour burden. Overall, for the first time, this study reveals that EVs can transfer mutant beta-catenin to the recipient cells and promote cancer progression.