转移性癌症在很大程度上是不可治愈的，也是癌症相关死亡的主要原因。转移性微环境有助于形成转移灶。与癌症相关的成纤维细胞 (CAFs) 通过介导炎性微环境起着关键作用，生成有利于转移的微环境。成纤维细胞还在调节细胞外基质 (ECM) 的结构和刚度方面起着核心作用。解决转移性微环境的早期变化有助于确定抑制转移进展的方法。在这里，我们在自发性乳腺癌肺转移的小鼠模型中证明，在癌前转移阶段出现了肺纤维化的变化和肺成纤维细胞的重塑，表明原发肿瘤对全身产生了影响。阿克汀 A (ActA) 是一个 TGFβ 超家族成员，从乳腺肿瘤中分泌，其在血液中的水平在携带肿瘤的小鼠中高度升高。ActA 上调了肺成纤维细胞中的纤维化促进因子的表达，导致肺癌前转移微环境中胶原沉积的增强。ActA 信号在肺转移中具有功能重要性，因为针对乳腺癌细胞中的 ActA 的基因靶向显著减轻了肺转移并改善了生存。此外，人类乳腺癌患者中高水平的 ActA 与肺转移复发和生存不良有关。该研究揭示了乳腺癌细胞通过系统性重塑转移灶中的基质微环境来促进肺转移的新机制。

Metastatic cancer is largely incurable and is the main cause of cancer-related deaths. The metastatic microenvironment facilitates formation of metastases. Cancer-associated fibroblasts (CAFs) are crucial players in generating a hospitable metastatic niche by mediating an inflammatory microenvironment. Fibroblasts also play a central role in modifying the architecture and stiffness of the extracellular matrix (ECM). Resolving the early changes in the metastatic niche could help identify approaches to inhibit metastatic progression. Here, we demonstrate in mouse models of spontaneous breast cancer pulmonary metastasis that fibrotic changes and rewiring of lung fibroblasts occurred at pre-metastatic stages, suggesting systemic influence by the primary tumor. Activin A (ActA), a TGFβ superfamily member, was secreted from breast tumors and its levels in the blood were highly elevated in tumor-bearing mice. ActA upregulated the expression of pro-fibrotic factors in lung fibroblasts, leading to enhanced collagen deposition in the lung pre-metastatic niche. ActA signaling was functionally important for lung metastasis, as genetic targeting of ActA in breast cancer cells significantly attenuated lung metastasis and improved survival. Moreover, high levels of ActA in human breast cancer patients were associated with lung metastatic relapse and poor survival. This study uncovers a novel mechanism by which breast cancer cells systemically rewire the stromal microenvironment in the metastatic niche to facilitate pulmonary metastasis.