Bone marrow–derived thrombospondin-1 programs tumor cell dormancy via CD47–integrin αvβ3 axis

Dormant disseminated tumor cells are responsible for late metastatic relapses, a current clinical challenge. This study investigates the microenvironmental signals that maintain breast cancer cell quiescence in the bone marrow. 4T1.2-CVp27 cells, engineered to enable quiescence detection, are used to assess the dormancy-inducing ability of bone marrow cells and thrombospondin-1 (TSP-1) domains, as well as to investigate the receptors and signaling pathways involved. The matricellular protein TSP-1 is a major mediator of breast cancer cell dormancy induction by the bone marrow. Among the different cell populations, endothelial cells and monocytes-macrophages induce quiescence via TSP-1. TSP-1 directly induces quiescence of tumor cells through the CD47–integrin αvβ3 receptor complex. Simultaneous engagement of CD47 and αvβ3 by the C-terminal, CaG fragment of TSP-1 causes inhibition of PKA which reprograms integrin signaling, diverting the canonical FAK–ERK proliferative pathway toward a p38-driven stress-adaptive, non-proliferative state while sustaining cell survival, a condition that characterizes dormancy. This signaling rewiring provides a mechanistic basis for how the bone marrow microenvironment maintains tumor cells in a quiescent state. Our findings identify the CD47–αvβ3 axis as a key mediator of metastatic dormancy and a potential therapeutic target for interventions aimed at targeting dormant cells thus preventing late relapse.