Human brain pericytes protect the blood–brain barrier from triple‐negative breast cancer cells while promoting tumor aggressiveness

The majority of breast cancer-related deaths result from metastatic progression, especially brain metastasis, associated with the poorest prognosis. Patients with triple-negative breast cancer (TNBC) are particularly prone to developing brain metastases. In this context, the blood-brain barrier (BBB) plays a pivotal role; however, the contribution of brain pericytes in mediating interactions between TNBC cells and the brain endothelial cells (ECs) remains unclear. To investigate the role of pericytes in modulating these interactions, we used a syngeneic human in vitro BBB model, composed of human brain-like endothelial cells (hBLECs) co-cultured with human brain pericytes (hBPs). Our findings demonstrate that hBPs secretions significantly reduce TNBC cell adhesion to hBLECs and protect the endothelium from TNBC cell-induced damage, both under normoxic and hypoxic conditions. Interestingly, we found that hBPs promote TNBC cell migration, invasion, and increase clonogenicity. Together, these findings uncover a dual role of brain pericytes in TNBC brain metastasis: they protect ECs and maintain BBB integrity against TNBC cells while simultaneously promoting tumor aggressiveness. Understanding this balance between protective and pro-metastatic functions may provide insights for developing novel therapeutic approaches to strengthen BBB defenses and limit brain colonization in TNBC patients.