An extramedullary bone model of metastatic dormancy reveals an increased rate of metastatic reactivation upon distant insults.

Bone metastatic relapse can emerge years after cancer diagnosis, driven by the reactivation of disseminated tumor cells (DTCs) that remain dormant in secondary organs. This behavior is controlled by the tissue microenvironment. We developed a tuneable, skeletal progenitor-based engineered extramedullary (EM) bone model in mice that closely mimics endogenous bone and induces dormancy in metastatic breast cancer cells. Within EM bone, cancer cells remained quiescent, with occasional transient proliferative episodes. Because the model integrates with host vasculature and permits controlled release of specific factors, it enables investigation of systemic influences on dormancy. Systemic inflammation, which increases bone marrow cell production, raised the proliferative fraction of dormant cells in EM bone and increased metastatic incidence in endogenous bone. We also identified high-mobility group box 2 (HMGB2) as a factor that promotes overt metastasis and is present in human bone metastases. Therefore, EM bone represents a powerful platform for studying metastatic dormancy.