Abstract P2-21-05: Vascular effects of Platelet-derived growth factor-B (PDGFB) in breast cancer metastasis to the brain

Abstract Brain metastases are associated with shortened survival and poorer quality of life in breast cancer patients. Recently, the importance of platelet-derived growth factor-B (PDGFB) and its stromally localized cognate receptor, platelet-derived growth factor receptor-beta (PDGFRβ) in promoting breast cancer metastasis to the brain was identified by our group. Historically, PDGFB-to-PDGFRβ signaling is known to promote angiogenesis and vessel maturation both in normal physiology and in cancer, but the mechanism(s) behind this tumor stromal interplay in brain metastasis is poorly understood. Based on our previous work and the work of others, we hypothesized that breast tumor-derived PDGFB directly modulates both brain endothelial and blood brain barrier (BBB) function by altering angiogenesis and endothelial permeability. To test this directly, we over-expressed PDGFB ligand in MDA-MB-231 and HCC1187 triple negative breast cancer cell lines and compared the angiogenic potential of the conditioned medium (CM) from these cells. We utilized both a 3D in vitro (human brain microvascular endothelial cell, HBMEC) spheroid angiogenesis model and a tri-culture BBB system (HBMECs in direct interaction with human astrocytes and human pericytes) to test the BBB vasculature. CM harvested from PDGFB overexpressing cells significantly increased the sprouting angiogenesis potential of 3D HBMECs and the migration of 3D tri-culture BBB spheroids compared to CM obtained from parental cells. In addition, CM from PDGFB overexpressing cells caused the surface of BBB spheroids to exhibit significantly increased permeability to high molecular weight dextran compared to CM from parental cells. In agreement with these findings, the tight junction protein ZO1 was diminished. Importantly, in vivo BBB permeability was also tested upon intracardiac injection of MDA-MB-231 cells with and without PDGFB overexpression. These studies revealed that Evans blue dye fluorescence intensity was significantly higher in the brains of mice injected with PDGFB overexpressing cells compared to parental cells. Overall, these studies reveal a previously unrecognized role for PDGFB-to-PDGFRβ signaling in brain vascular remodeling and BBB permeability, which has clinical implications for women with PDGFB-positive breast cancer. Citation Format: Sajita Shah, Rebecca Packard, Sarah Steck, Alexis Mossing, Yalini Ramamoorthy, Katie Thies, Alexander Didier, Jonathan Spehar, Dillon Richardson, Tasneem Arsiwala, Jonathan Godbout, Steven Sizemore, Paul Lockman, Gina Sizemore. Vascular effects of Platelet-derived growth factor-B (PDGFB) in breast cancer metastasis to the brain [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-21-05.