TMIC-58. A New View of Microvascular Proliferation: PDGFRB+ Perivascular Stromal Cells Drive MVP Formation, Immunosuppression and Stemness in Glioblastoma

Abstract Microvascular proliferation (MVP), a hallmark of glioblastoma (GBM), is characterized by hyperplastic vasculature with glomerular-like features, constituting a GBM-specific perivascular niche (PVN). Our recently published work challenged the current dogma that MVP is attributed to endothelial cell hyperplasia by demonstrating that MVP is composed of Glioma-associated-mesenchymal stem cells (GA-MSCs), pericytes, cancer-associated fibroblasts (CAFs), and smooth muscle cells (SMCs), collectively called perivascular stromal cells (PVSCs) (Poon et al. 2025). PVSCs express Platelet-derived Growth Factor Receptor-beta (PDGFRB), which is found on no other cells in GBMs. RNA trajectory analyses suggest PDGFRB+ PVSCs differentiate from GA-MSCs, underscoring the central role of GA-MSCs in MVP. Spatial transcriptomics revealed interaction of PDGFRB+ PVSCs with pro-tumor macrophages, suggesting a role in immunosuppression. To move from correlative to functional analyses of PDGFRB+ PVSCs in MVP we undertook a reverse-translational approach using immunocompetent murine GBM models. Specifically, GFP-labeled GSC005-tumor cells were implanted into the brains of C57BL/6 mice. When moribund, tumors were removed and tumor (GFP+), immune (CD45+), and non-tumor/non-immune (GFP−/CD45−) compartments were analyzed by scRNA-seq, which demonstrated that PDGFRB+ cells are exclusively in the non-tumor/non-immune compartment. Clustering revealed four PDGFRB+ PVSC populations, GA-MSCs, CAFs, pericytes, and SMCs, corroborating our human-tissue data. Xenium-guided spatial transcriptomics data, annotated with IVY Glioblastoma-Atlas signatures, showed that PDGFRB+ PVSCs were enriched in MVP regions (p<0.05). PDGFRB+ PVSCs also co-localized with tumor-associated macrophages (p<0.05) and anti-inflammatory monocytes (p<0.05), indicating a role in immunosuppression. Glioma stem cells (GSCs) interacted with PDGFRB+ PVSCs (p<0.05) and exhibited high stemness scores. Multiplex immunofluorescence validated these spatial relationships. Together, our results in mouse GSC005 corroborate our human data and provide compelling evidence that PDGFRB+ PVSCs, particularly GA-MSCs, drive MVP formation and lead to immunosuppression and GSC-maintenance. These data challenge current endothelial-centric dogma about the composition of MVP in gliomas and suggest a new PVSC-centric model.