Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalizationMonocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.
Single-cell transcriptomic analysis reveals the functional heterogeneity and clinical signification of pericyte subpopulations in gliomasYing Guo, Yuqi Liu, Xiao-Ning Zhang et al.|Research Square|2023 Abstract Gliomas are not only among the most vascular-rich solid tumors, but also the most common primary brain tumors. The vascular morphology and molecular characteristics of gliomas are heterogeneous. Pericytes are one of the important cell components in glioma vascular structure and are highly heterogenies. However, the heterogeneity of pericytes in gliomas is not clear, and the biological characteristics and clinical significance of different subpopulations of pericytes are still unknown. An in-depth understanding of pericyte characteristics based on gene expression profiling, as well as the correlation of pericytes and the clinical prognosis of glioma are important prerequisites for the development of follow-up targeted vascular therapy. In this study, the heterogeneity of pericytes in glioma was revealed by single-cell RNA sequencing technique, the relationship between pericyte subpopulations and patient survival, prognosis and treatment response were clarified, and the MMP9 + pericytes were identified as a unique pericyte subpopulation in the core area of glioma, providing theoretical basis for analyzing the characteristics of vascular microenvironment of glioma and new targets for anti-vascular therapy of glioma.