Breast cancer-secreted factors promote lung metastasis by signaling systemically to induce a fibrotic pre-metastatic niche.

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.