Mutations in β-catenin, especially at the residues critical for its degradation, render it constitutively active. Here, we show that mutant β-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 β-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 β-catenin. SILAC-based quantitative proteomics analysis confirmed the transfer of mutant β-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 β-catenin to the recipient cells and promote cancer progression.

β-catenin的突变，尤其是对其降解至关重要的残基处的突变，使其具有组成型活性。在这里，我们显示突变β-连环蛋白可以通过细胞外囊泡（EV）转运并激活受体细胞中的Wnt信号通路。完整的蛋白质组学分析确定了结直肠癌（CRC）细胞分泌的EV中存在β-catenin突变。后续实验确定，从LIM1215 CRC细胞释放的EVs用野生型β-catenin刺激受体细胞中的Wnt信号通路。基于SILAC的定量蛋白质组学分析证实了突变型β-catenin转移到受体细胞的核中。体内在植入RKO CRC细胞的小鼠中追踪DiR标记的EV揭示了其生物分布，证实了肿瘤细胞中Wnt信号通路的激活并增加了肿瘤负担。总体而言，这项研究首次揭示了电动汽车可以将突变的β-连环蛋白转移至受体细胞并促进癌症进展。