Cancer cells release extracellular vesicles (EVs) that contain functional biomolecules such as RNA and proteins. EVs are transferred to recipient cancer cells and can promote tumour progression and therapy resistance. Through RNAi screening, we identified a novel EV uptake mechanism involving a triple interaction between the chemokine receptor CCR8 on the cells, glycans exposed on EVs and the soluble ligand CCL18. This ligand acts as bridging molecule, connecting EVs to cancer cells. We show that glioblastoma EVs promote cell proliferation and resistance to the alkylating agent temozolomide (TMZ). Using in vitro and in vivo stem-like glioblastoma models, we demonstrate that EV-induced phenotypes are neutralised by a small molecule CCR8 inhibitor, R243. Interference with chemokine receptors may offer therapeutic opportunities against EV-mediated cross-talk in glioblastoma.

癌细胞释放含有功能性生物分子（例如 RNA 和蛋白质）的细胞外囊泡 (EV)。 EV 被转移到受体癌细胞中，可以促进肿瘤进展和治疗耐药性。通过RNAi筛选，我们发现了一种新的EV摄取机制，涉及细胞上的趋化因子受体CCR8、EV上暴露的聚糖和可溶性配体CCL18之间的三重相互作用。该配体充当桥接分子，将 EV 与癌细胞连接起来。我们发现胶质母细胞瘤 EV 促进细胞增殖和对烷化剂替莫唑胺 (TMZ) 的耐药性。使用体外和体内干细胞样胶质母细胞瘤模型，我们证明小分子 CCR8 抑制剂 R243 可以中和 EV 诱导的表型。干扰趋化因子受体可能为胶质母细胞瘤中 EV 介导的串扰提供治疗机会。