Bone mineral density affects tumor growth by shaping microenvironmental heterogeneity.

Breast cancer bone metastasis is the leading cause of mortality in patients with advanced breast cancer. Although decreased mineral density is a known risk factor for bone metastasis, the underlying mechanisms remain poorly understood because studying the isolated effect of bone mineral density on tumor heterogeneity is challenging with conventional approaches. Here, we investigate how bone mineral content affects tumor growth and microenvironmental complexity by combining single-cell RNA-sequencing with mineral-containing or mineral-free decellularized bone matrices. We discover that the absence of bone mineral significantly influences fibroblast and immune cell heterogeneity, promoting phenotypes that increase tumor growth and alter the response to injury or disease. Importantly, we observe that the stromal response to matrix mineral content depends on host immunocompetence and the murine tumor model used. Collectively, our findings suggest that bone mineral density affects tumor growth by altering microenvironmental complexity in an organism-dependent manner.