癌症与特定器官的转移有关，同时不影响其他器官。乳腺癌表现为肺转移，但很少出现肾转移。以这种差异为例，我们询问了器官特异性转移倾向背后的机制。我们使用转移性乳腺癌的自发和植入模型以及炎症组织纤维化、单细胞测序分析和功能研究来揭示器官特异性转移的因果决定因素。在这里，我们发现血管生成素 2 (Ang2) 介导的肺特异性内皮紧密连接蛋白 Claudin 5 的抑制促进了肺转移，炎症纤维化微环境增强了这种抑制，并被抗 Ang2 阻断抗体阻止，同时肾转移被阻止由非 Ang2 反应性 Claudins 2 和 10 抑制。抑制 Claudins 2 和 10 足以诱导肾转移的出现。这项研究说明了器官特异性血管异质性在决定器官性转移方面的影响，与癌细胞内在机制无关。© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

Carcinomas are associated with metastasis to specific organs while sparing others. Breast cancer presents with lung metastasis but rarely kidney metastasis. Using this difference as an example, we queried the mechanism(s) behind the proclivity for organ-specific metastasis. We used spontaneous and implant models of metastatic mammary carcinoma coupled with inflammatory tissue fibrosis, single-cell sequencing analyses and functional studies to unravel the causal determinants of organ-specific metastasis. Here we show that lung metastasis is facilitated by angiopoietin 2 (Ang2)-mediated suppression of lung-specific endothelial tight junction protein Claudin 5, which is augmented by the inflammatory fibrotic microenvironment and prevented by anti-Ang2 blocking antibodies, while kidney metastasis is prevented by non-Ang2-responsive Claudins 2 and 10. Suppression of Claudins 2 and 10 was sufficient to induce the emergence of kidney metastasis. This study illustrates the influence of organ-specific vascular heterogeneity in determining organotropic metastasis, independent of cancer cell-intrinsic mechanisms.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.