Sznurkowska, M. K.; Castro-Giner, F.; Zhang, Y.; Ring, A.; Schwab, F. D.; Albrecht, F.; Mertz, K. D.; Strittmatter, K.; Ozimski, L. L.; Budinjas, S.; Auray, G.; Giachino, C.; Taylor, V.; Gvozdenovic, A.; Malanchi, I.; Frauchiger-Heuer, H.; Wicki, A.; Vetter, M.; Aceto, N.

Breast cancer progression to visceral organs such as lung and liver is regarded as a dreadful event, unequivocally associated with a poor prognosis. Yet, these vital sites are characterized by highly diverse cellular microenvironments and physiological functions, suggesting that they may influence cancer cells behavior in divergent ways. Unexpectedly, we find that while the liver microenvironment fosters metastasis-boosting properties of its metastatic seeds and favors secondary spread, the lungs impose a drastic roadblock to the same processes. Using patient data and mouse models of breast cancer that spontaneously metastasize to visceral organs, coupled with genetic barcode-mediated metastasis tracing, niche labeling technology and single cell analysis of both tumor cells and their direct microenvironment at each site, we characterize this dichotomy and identify differential microenvironmental factors that contribute to liver vs lung metastasis biology. Mechanistically, we uncover pulmonary cytokines, such as Granulin, whose activity naturally blocks metastatic properties. Conversely, we identify BMP2-producing endothelial cells within the liver metastatic niche, capable to enhance further spread. Together, we reveal an unexpected contrast in the site-specific behavior of visceral metastases in triple-negative breast cancer models, highlighting microenvironmental factors that contribute to its geographical diversity, as well as organ-specific opportunities for intervention.