The liver niche accelerates, while the lung niche restrains secondary spread of breast cancer.

Breast cancer progression to visceral organs such as the lung and liver is associated with poor prognosis. Yet, these organs have diverse cellular microenvironments that may differentially influence cancer cell behavior. Here, we show that breast cancer metastases differ in their capacity for secondary seeding: the liver fosters metastasis-promoting properties and boosts secondary spread, whereas the lung restricts these processes, favoring local growth. Using patient data and rapid autopsy tissues, mouse models with barcode-mediated tracing, niche-labeling technology, and single-cell analysis of tumor cells and their direct microenvironment, we dissect the cellular and molecular microenvironmental factors underlying this differential behavior. Mechanistically, we identify BMP2-producing endothelial cells as critical players within the liver metastatic niche, enhancing metastasis-to-metastasis dissemination. Targeting the BMP2 signaling axis suppresses secondary spread of liver-derived breast cancer lesions. Altogether, we reveal site-specific behavior of lung and liver metastases in breast cancer, highlighting microenvironmental mechanisms and therapeutic opportunities for intervention.