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

Le résumé fourni par la source

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.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.