Mineralized bone matrix attenuates breast cancer cell malignancy by altering MSC mechanoregulation

Bone metastasis, the leading cause of death in breast cancer patients with metastatic disease, initiates by early dissemination of cancer cells to osteogenic niches containing mineralizing collagen matrix and mesenchymal stem cells (MSCs). How collagen mineralization affects MSC phenotype and what consequences these changes have on cancer cells remains unclear. Understanding these links is critical as MSCs regulate cancer cell growth and because decreased bone mineral density increases the risk for bone metastasis. Using biofunctional bone matrix models, we find that mineralization prevents MSC-mediated collagen remodeling by limiting actomyosin contractility while promoting osteogenic differentiation. In the absence of mineral, MSCs develop a profibrotic phenotype that supports breast cancer cell malignancy in vitro and in vivo. These findings highlight that collagen mineralization stimulates MSC osteogenic differentiation by inhibiting profibrotic matrix remodeling rather than by inducing stiffness-dependent mechanosignaling. Collagen mineralization may, therefore, play a key role in regulating whether osteogenic niches provide a favorable or restrictive environment for early stages of metastasis.