Tumor exosome integrins determine organotropic metastasis

Stephen Paget first proposed, in 1889, that organ distribution of metastases is a non-random event, yet metastatic organotropism remains one of the greatest mysteries in cancer biology. Here, we demonstrate that exosomes released by lung-, liver- and brain-tropic tumor cells fuse preferentially with resident cells at their predicted destination, such as fibroblasts and epithelial cells in the lung, Kupffer cells in the liver, and endothelial cells in the brain. We found that exosome homing to organ-specific cell types prepares the pre-metastatic niche and that treatment with exosomes derived from lung tropic models can redirect metastasis to the lung. Proteomic profiling of exosomes revealed distinct integrin expression patterns associated with each organ-specific metastasis. Whereas exosomal integrins α6β4 and α6β1 were associated with lung metastasis, exosomal integrins αvβ5 and αvβ3 were linked with liver and brain metastases, respectively. Targeting α6β4 and αvβ5 integrins decreased exosome uptake and metastasis in the lung and liver, respectively. Importantly, we demonstrate that exosome uptake activates a cell-specific subset of S100 family genes, known to support cell migration and niche formation. Finally, our clinical data indicate that integrin-expression profiles in circulating plasma exosomes from cancer patients could be used to predict organ-specific metastasis. Education of human von Kupffer cells in vitro with human pancreatic cancer exosomes

1889年，斯蒂芬·佩吉特（Stephen Paget）首次提出，肿瘤转移的器官分布并非随机事件，然而转移器官嗜性(metastatic organotropism)仍是癌症生物学领域最具挑战性的未解谜题之一。本研究证实，肺嗜性、肝嗜性及脑嗜性肿瘤细胞释放的外泌体(exosomes)，会优先与其预期定植器官的驻留细胞发生融合——例如肺部的成纤维细胞与上皮细胞、肝脏的库普弗细胞(Kupffer cells)以及脑部的内皮细胞。我们发现，外泌体向器官特异性细胞的归巢可塑造预转移微环境，且经肺嗜性模型来源的外泌体处理后，可将肿瘤转移重定向至肺部。对于外泌体的蛋白质组学分析(proteomic profiling)显示，其存在与各器官特异性转移相关的独特整合素(integrin)表达谱。其中，外泌体整合素α6β4与α6β1与肺转移相关，而αvβ5、αvβ3整合素则分别与肝转移及脑转移相关。靶向α6β4与αvβ5整合素，可分别降低外泌体在肺部与肝脏的摄取量，并抑制相应部位的肿瘤转移。尤为重要的是，本研究证实，外泌体的摄取会激活细胞特异性的S100家族基因子集，而这类基因已被证实可促进细胞迁移与微环境形成。最后，本研究的临床数据表明，癌症患者循环血浆中外泌体的整合素表达谱，可用于预测肿瘤的器官特异性转移。体外利用人胰腺癌来源外泌体致敏人库普弗细胞。