ICAM1-Mediated Endothelial Cells and Macrophage Interactions in Modulating GBM Malignant Transformation

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Glioblastoma (GBM) frequently recurs, posing a significant challenge in brain tumor treatment.
• Endothelial cells are key components of the tumor microenvironment (TME) in primary GBM, but their specific role in recurrent GBM (rGBM) is not well understood.

Purpose of the Study:

• To investigate the role of endothelial cells in the tumor microenvironment of recurrent glioblastoma.
• To identify molecular mechanisms driving GBM recurrence and potential therapeutic targets.

Main Methods:

• Single-cell RNA sequencing analysis of endothelial cells from GBM patient data.
• Differential gene expression and pseudotime trajectory analysis to identify key genes.
• TCGA data validation, immunofluorescence, gene knockdown, and co-culture experiments to explore cellular crosstalk.

Main Results:

• Two distinct endothelial cell clusters were identified, with one associated with poorer prognosis in rGBM.
• Intercellular adhesion molecule-1 (ICAM1) was identified as a key gene upregulated by hypoxia in rGBM endothelial cells, facilitating macrophage recruitment.
• A feedback loop was observed where endothelial-derived CCL2 induced macrophage-derived adrenomedullin (ADM), promoting angiogenesis and tumor cell proliferation/migration.

Conclusions:

• Hypoxia-induced ICAM1 upregulation in endothelial cells contributes to macrophage recruitment in rGBM.
• Endothelial-macrophage crosstalk, mediated by CCL2 and ADM, creates a pro-tumorigenic loop in the rGBM microenvironment.
• These findings provide mechanistic insights into rGBM progression and suggest potential therapeutic strategies targeting this axis.