Bone Metastasis Initiation Is Coupled with Bone Remodeling through Osteogenic Differentiation of NG2⁺ Cells

The bone microenvironment is dynamic and undergoes remodeling in normal and pathologic conditions. Whether such remodeling affects disseminated tumor cells (DTC) and bone metastasis remains poorly understood. Here, we demonstrated that pathologic fractures increase metastatic colonization around the injury. NG2⁺ cells are a common participant in bone metastasis initiation and bone remodeling in both homeostatic and fractured conditions. NG2⁺ bone mesenchymal stem/stromal cells (BMSC) often colocalize with DTCs in the perivascular niche. Both DTCs and NG2⁺ BMSCs are recruited to remodeling sites. Ablation of NG2⁺ lineage impaired bone remodeling and concurrently diminished metastatic colonization. In cocultures, NG2⁺ BMSCs, especially when undergoing osteodifferentiation, enhanced cancer cell proliferation and migration. Knockout of N-cadherin in NG2⁺ cells abolished these effects in vitro and phenocopied NG2⁺ lineage depletion in vivo. These findings uncover dual roles of NG2⁺ cells in metastasis and remodeling and indicate that osteodifferentiation of BMSCs promotes metastasis initiation via N-cadherin–mediated cell–cell interaction.