Molecular Determinants of Macrophage Polarization in Glioblastoma and Implications for Tumor Progression

TL;DR

This study explores how macrophages in glioblastoma tumors shift to a tumor-supporting state, identifying key genes and suggesting new therapeutic strategies.

Contribution

The study identifies specific macrophage-related genes and mechanisms driving M2 polarization in glioblastoma, offering novel therapeutic insights.

Findings

Macrophage infiltration in GBM correlates with poor prognosis and is associated with 41 risk genes.

Nine key macrophage-specific genes were validated, including SPP1, CD74, and C3.

Overexpression of CD74, CLEC7A, and IFI30 enhances M2 polarization and tumor-promoting functions.

Abstract

Glioblastoma (GBM) is a highly aggressive brain tumor with a complex tumor microenvironment (TME) that includes immune cell infiltration, notably macrophages. The role of macrophages in GBM progression is influenced by their polarization state, which can be either pro-inflammatory (M1) or immunosuppressive (M2). This study investigates the macrophage polarization in GBM, identifying key macrophage-related genes and their impact on tumor progression. Analysis of TCGA-GBM data revealed that macrophage infiltration correlates with poor prognosis, with 41 risk-associated genes identified. DSP dataset analysis highlighted 378 differentially expressed genes between CD68+ macrophages and GFAP+ controls, including immune-related genes like SPP1, CD74, and C3. Cross-validation with single-cell RNA-seq confirmed the expression of 9 key genes, with 7 genes being macrophage-specific. In vitro experiments using conditioned media from GBM cell lines demonstrated that GBM cells promote macrophage polarization towards an M2-like phenotype. Overexpression of CD74, CLEC7A, and IFI30 in macrophages further enhanced M2 polarization, which was associated with increased tumor-promoting functions, including enhanced invasion and reduced apoptosis in GBM cells. Together, these findings highlight the role of M2 macrophage polarization in promoting GBM progression and suggest that targeting macrophage polarization pathways may offer therapeutic potential.

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