TMIC-75. TUMOR ENDOTHELIAL CELL-DERIVED ASPORIN DIFFERENTIALLY REGULATES GLIOBLASTOMA GROWTH

Abstract

Abstract Gliomas are the most prevalent and malignant brain tumors. A major histopathological feature that distinguishes the high-grade (IV) glioblastoma (GBM) from slow-growing low-grade (II and III) glioma is microvascular hyperproliferation. Although gliomas are highly vascularized tumors, anti-angiogenic therapies have failed to prevent recurrence and significantly improve patient survival. To determine if tumor endothelial cells (TEC) display molecular heterogeneity, we performed bulk RNA-sequencing on cultured CD31+ TEC from low-grade (II/III), and high-grade (IV, primary and recurrent) gliomas. Low- and high-grade TEC exhibited significant molecular heterogeneity, with increased enrichment of extracellular matrix and cell cycle-related gene sets in low-grade and enrichment of cytokine and immune response-related gene sets in high-grade TEC. We also found significant functional differences in proliferation capacity, and resistance to anti-angiogenic therapies between low-and high-grade TEC. Co-transplantation of low-grade TEC with tumor cells significantly inhibited GBM growth and enhanced survival, whereas high-grade TEC promoted growth of tumors in orthotopic xenografts in vivo. Differential gene expression analysis revealed several proteoglycans distinctly expressed by low-grade TEC. Of the highly enriched molecules in low-grade TEC, Asporin (ASPN), a small leucine-rich repeat proteoglycan (SLRP) significantly inhibited growth and proliferation of IDH1-wt GBM cells but did not affect IDH1-mutant tumor cells. Co-transplantation of TEC-lacking ASPN with IDH1-wt GBM partially rescued the growth-inhibitory effect of low-grade TEC on tumor growth and reduced survival. Ongoing experiments are aimed at determining the molecular mechanism underlying the growth-inhibitory effects of TEC-derived Asporin on glioma.