BSBM-08 ASTROCYTE PDGFRβ HYPERACTIVATION IN BREAST CANCER BRAIN METASTASIS

Abstract Advances in treating primary breast tumors and extracranial metastases have inadvertently led to a rise in brain metastases, which are severe and carry bleak prognostic outcomes. Thus, there is an urgent need to investigate the cellular and molecular drivers of metastatic central nervous system (CNS) tumors. The tumor microenvironment (TME) is critically important for metastasis, as metastatic cells must alter their new environment to survive and grow. Our laboratory's recent studies have pinpointed platelet-derived growth factor receptor beta (PDGFRβ) signaling as a critical pathway in promoting breast cancer-associated brain metastases (BCBM). Key findings from this published work involved data emanating from a genetically engineered mouse model (GEMM) with hyperactive PDGFRβ-D849V in the mesenchymal lineage driven by Fsp1-cre. These mice exhibit increased BCBM when injected with murine mammary tumor cells secreting the ligand PDGFB, making them an effective model for studying BCBM. However, hyperactivity of PDGFRβ in these mice occurs in all mesenchymal cells. To investigate cell-specific PDGFRβ functions in the CNS, we analyzed publicly available single-cell RNA-seq data of the adult murine brain. This analysis identified astrocyte populations expressing both Pdgfrb and the Fsp1/S100A4 mesenchymal lineage marker. To probe the role of PDGFRβ in reactive astrocytes, we developed a Gfap-cre GEMM model crossed with our mutant PDGFRβ hyperactivation allele (Gfap-cre;Pdgfrb-D849V). These mice exhibit increased GFAP expression in the absence of tumor and decreased overall survival upon intracardiac injection of PDGFB secreting breast cancer cells. Furthermore, flow cytometry at day 10 post intracardiac injection indicates potential differences in the immune response of the brain TME compared to controls. Current work is focused on identifying specific transcriptomic changes in astrocyte populations due to both PDGFRβ hyperactivation as well as metastatic breast cancer colonization of the brain. Overall, this work aims to identify potential therapeutic targets to treat BCBM.