Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Department of Biomolecular Sciences, Weizmann Institute of Science, Tel Aviv, Israel.
Cancer Res. 2023 Oct 13;83(20):3354-3367. doi: 10.1158/0008-5472.CAN-22-3707.
Metastatic cancer is largely incurable and is the main cause of cancer-related deaths. The metastatic microenvironment facilitates formation of metastases. Cancer-associated fibroblasts (CAF) 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 premetastatic 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 profibrotic factors in lung fibroblasts, leading to enhanced collagen deposition in the lung premetastatic 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 patients with breast cancer 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.
ActA mediates cross-talk between breast cancer cells and cancer-associated fibroblasts in the lung metastatic niche that enhances fibrosis and metastasis, implicating ActA as a potential therapeutic target to inhibit metastatic relapse.
转移性癌症在很大程度上是无法治愈的，也是癌症相关死亡的主要原因。转移性微环境促进了转移的形成。癌症相关成纤维细胞（CAF）通过介导炎症微环境，是产生有利于转移的小生境的关键参与者。成纤维细胞在修饰细胞外基质（ECM）的结构和硬度方面也起着核心作用。解析转移小生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，纤维化改变和肺成纤维细胞的重布线发生在转移前阶段，这表明原发性肿瘤具有系统影响。激活素 A（ActA）是 TGFβ 超家族成员，从乳腺癌肿瘤中分泌，其在荷瘤小鼠血液中的水平显著升高。ActA 上调了肺成纤维细胞中促纤维化因子的表达，导致肺转移前小生境中胶原沉积增加。ActA 信号在肺转移中具有功能重要性，因为乳腺癌细胞中 ActA 的基因靶向显著减弱了肺转移并提高了存活率。此外，人类乳腺癌患者中高水平的 ActA 与肺转移复发和预后不良相关。这项研究揭示了一种新的机制，即乳腺癌细胞通过系统性重排转移小生境中的基质微环境来促进肺转移。
ActA 介导乳腺癌细胞与肺转移小生境中的癌症相关成纤维细胞之间的串扰，增强纤维化和转移，表明 ActA 可能是抑制转移复发的潜在治疗靶点。
