BSBM-07 PDGFB-TO-PDGFRβ SIGNALING IMPACTS BLOOD-BRAIN BARRIER INTEGRITY AND ANGIOGENESIS IN BREAST CANCER BRAIN METASTASIS

Abstract Breast cancer associated brain metastases (BCBM) confer a particularly poor prognosis, with a median survival time of 10-11 months and decreased quality of life. Our group recently determined that platelet-derived growth factor-B (PDGFB) and its receptor, platelet-derived growth factor receptor-beta (PDGFRβ) promote BCBM; however, the underlying cellular and molecular mechanisms which drive this process are still unclear. PDGFB-to-PDGFRβ signaling is a well-known regulator of angiogenesis and blood vessel maturation in normal physiological and pathological conditions. Here, we investigated the impact of PDGFB-to-PDGFRβ signaling on the vascular integrity in the brain. Breast cancer (BC) cell lines were engineered to overexpress PDGFB and conditioned media from control and PDGFB cells were evaluated in brain microvasculature angiogenesis, blood-brain barrier (BBB) integrity, and permeability assays. In vivo intracardiac injection of BC cell lines into immunodeficient mice were used to evaluate BBB permeability and vascular disruption. PDGFB overexpression in BC cells did not affect proliferation and invasion but did induce human brain microvascular endothelial cells (HBMEC) sprouting, BBB impairment, and increased BBB permeability in 3D models. Mechanistically, PDGFB disrupted tight junction proteins in brain endothelial cells. In vivo experiments confirmed PDGFB-mediated disruption of the BBB correlates with increased uptake of Evan’s blue dye into the brain parenchyma. Transcriptomic analysis of BCBM patients revealed enrichment of angiogenesis-related gene sets in tumors with high PDGFB expression, implicating PDGFB in BCBM pathophysiology. In summary, our study provides compelling evidence that PDGFB signaling contributes to the capability of BC cells to disrupt BBB and vasculature by compromising BBB integrity and enhancing angiogenesis. These findings highlight the potential of targeting this signaling as a therapeutic strategy in BCBM. Further research is warranted to explore the therapeutic implications of these findings and to develop targeted interventions that can disrupt this signaling pathway.