The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.

中文翻译：

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肿瘤外泌体 CEMIP 蛋白促进脑转移中癌细胞的定植。

目前，由于我们对驱动脑转移的分子机制的理解存在局限性，因此阻碍了针对脑转移的有效疗法的开发。在这里，我们定义了肿瘤分泌的外泌体对脑转移定植的贡献，并证明用来自脑转移细胞的外泌体对脑微环境进行预处理可以增强癌细胞的生长。蛋白质组学分析确定细胞迁移诱导和透明质酸结合蛋白 (CEMIP) 在来自脑转移的外泌体中升高，但在肺或骨转移细胞中没有升高。肿瘤细胞中的 CEMIP 消耗会损害脑转移，破坏侵袭和肿瘤细胞与脑血管系统的关联，通过用 CEMIP+ 外泌体预处理脑微环境来拯救表型。而且，脑内皮细胞和小胶质细胞摄取 CEMIP+ 外泌体通过上调由 Ptgs2、Tnf 和 Ccl/Cxcl 编码的促炎细胞因子诱导血管周围生态位的内皮细胞分支和炎症，已知这些细胞因子可促进脑血管重塑和转移。CEMIP 在脑转移患者的肿瘤组织和外泌体中升高，并预测脑转移进展和患者存活率。总的来说，我们的研究结果表明，靶向外泌体 CEMIP 可能构成预防和治疗脑转移的未来途径。CEMIP 在脑转移患者的肿瘤组织和外泌体中升高，并预测脑转移进展和患者存活率。总的来说，我们的研究结果表明，靶向外泌体 CEMIP 可能构成预防和治疗脑转移的未来途径。CEMIP 在脑转移患者的肿瘤组织和外泌体中升高，并预测脑转移进展和患者存活率。总的来说，我们的研究结果表明，靶向外泌体 CEMIP 可能构成预防和治疗脑转移的未来途径。