Abstract

Bone metastasis is a leading cause of death among patients with advanced breast cancer, but the mechanisms controlling tumor cell phenotype in the skeleton remain elusive. In particular, it is unknown how bone matrix mineralization dictates cellular entry to latency or metastatic outgrowth. Understanding these connections is critical given that tumor cells often disseminate to regions of active mineralization. Using biofunctional models of bone matrix, we show that matrix mineralization is a critical and largely overlooked component determining the early-stage development of bone metastases. Contradicting the conventional assumption that rigidity stimulates metastatic progression, we found that tumor cell proliferation changes with matrix mineralization where higher mineral levels, which increased rigidity, induced quiescence by reducing mechanosignaling. This matrix-inducible phenotype is durable to changes in mineral content and translated to reduced tumor growth in vivo and patient mortality. Our results suggest that methods to maintain physiological bone matrix mineralization could be leveraged clinically to promote quiescence in patients with advanced disease and that models for studies of bone metastasis should integrate mineral as a key design parameter.