A NET-related gene signature characterizes prognosis and immune features in glioma

Description

Objective: To develop and validate a neutrophil extracellular trap (NET)-related prognostic signature for glioma and investigate its associations with patient survival, the tumor immune microenvironment, drug activity, and the potential role of MMP9 in NET formation. Methods: Transcriptomic and clinical data from the TCGA, CGGA, and Rembrandt glioma cohorts were used to construct and validate an eight-gene NET-related prognostic signature. Associations with survival, immune/stromal infiltration, immune-related features, and drug-activity profiles were evaluated. MMP9 was further examined using an in-house glioma cohort, neutrophil–glioma cell co-culture experiments, and an orthotopic glioma model established in female Wistar rats. Results: The eight-gene signature consistently stratified patients into groups with distinct survival outcomes across all three cohorts. High-risk tumors exhibited greater inferred immune and stromal infiltration, enrichment of several pro-tumor immune cell populations, and increased expression of immune-checkpoint-related transcripts. CellMiner analysis identified associations between signature-gene expression and the activity of several anticancer agents. MMP9 was elevated in glioma tissues and associated with poor outcome. MMP9 overexpression was accompanied by increased NET formation and enhanced glioma cell proliferation, migration, and invasion in co-culture, as well as greater tumor growth and increased neutrophil/NET-associated markers in vivo. Conclusion: The NET-related signature is associated with adverse prognosis and an immune-rich glioma microenvironment. MMP9 may contribute to NET formation and glioma progression, although further mechanistic and prospective validation is required.

Institutions

• Wenzhou Medical University

  Zhejiang, Wenzhou

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