Oncogenic drivers shape the tumor microenvironment in human gliomas

Area of Science:

• Neuro-oncology
• Genomics
• Cancer Biology

Background:

• Gliomas are aggressive brain tumors with poorly understood tumor microenvironments.
• Oncogenic mutations significantly impact glioma progression but their influence on the microenvironment is unclear.

Purpose of the Study:

• To investigate how genomic alterations influence the glioma microenvironment.
• To define the impact of major driver mutations on spatial tumor organization.

Main Methods:

• Integrative multiomic and spatial transcriptomic analysis of 93 glioma samples.
• Whole-genome sequencing, Hi-C, RNA-seq, and Xenium single-cell spatial transcriptomics were employed.
• Comparison of IDH-mutant gliomas and IDH-wildtype glioblastomas, including analysis of EGFR amplification modes (ecDNA vs. linear).

Main Results:

• IDH-mutant gliomas exhibited inflammatory microglia (CX3CR1+) in astrocyte-like malignant neighborhoods.
• Glioblastomas showed increased T-cell infiltration and immunosuppressive myeloid cells.
• EGFR ecDNA-driven glioblastomas displayed mesenchymal-like cells and increased pericyte-malignant cell interactions, linked to hypoxia and vascular proliferation.

Conclusions:

• The mode of oncogene amplification (linear vs. ecDNA) dictates distinct glioma architectures and transcriptional dynamics.
• Oncogenic drivers significantly shape the glioma microenvironment, creating subtype-specific cellular ecosystems.
• Findings provide insights for developing targeted therapeutic strategies for gliomas.