# Determining the Biological Features of Aggressive Meningioma Growth with Transcriptomic Profiling

## TL;DR

This study identifies biological features linked to aggressive meningioma growth by analyzing gene expression across different tumor grades.

## Contribution

The study reveals novel insights into metabolic reprogramming and immune regulation in aggressive meningiomas.

## Key findings

- High-grade meningiomas show increased cell proliferation and metabolic changes involving phosphoglycerate kinase 1.
- Benign meningiomas are enriched for cell morphogenesis and immune regulation processes.
- Border-associated macrophages decrease progressively with increasing tumor grade.

## Abstract

Meningiomas are frequently diagnosed tumors of intracranial location. In the WHO classification, tumor aggressiveness is assessed by assigning increasing grades, with WHO grade I tumors considered benign and WHO grade III tumors the most aggressive. In our study, we aimed to identify biological features associated with meningioma aggressiveness by profiling gene expression in tumor samples of different WHO grades (I, II, and III). We first identified genes with grade-related expression and subsequently analyzed their roles through biological pathway analysis and by estimating the cellular composition of the heterogeneous tumor samples. The results reflect well-established features of aggressive growth, such as increased cell proliferation, but also highlight less well-characterized aspects of tumor biology including alterations in cellular metabolism involving phosphoglycerate kinase 1, changes in transmembrane ion transport, and differences in the abundance of border-associated macrophages, which represent key distinctions between benign and aggressive meningiomas.

Background: Meningiomas are common intracranial tumors in adults. Most are benign WHO grade I (GI) tumors, while approximately 20% are diagnosed as more aggressive WHO grade II (GII) and grade III (GIII) meningiomas. The study aimed to identify genes with tumor grade-related expression and to assess their functional relevance. Methods: RNA sequencing (RNA-seq) was performed to analyze transcriptomes of benign meningothelial (n = 19) and fibrous (n = 11), atypical (n = 18) and anaplastic (n = 12) meningiomas. The data were analyzed for differential genes expression and Gene Set Enrichment Analysis (GSEA). A deposited scRNA-seq dataset was used to define meningioma cellular composition and cell type-specific gene expression enabling deconvolution of RNA-seq data. Results: Unsupervised analysis revealed three tumor clusters corresponding to the histological subtypes of meningothelial (GI), fibrous (GI) and atypical/anaplastic (GII/GIII) meningiomas. Differential analysis identified 5518 protein-coding genes with grade-related changes in expression. GSEA showed that high-grade meningiomas were enriched for processes of cell proliferation, ribosome biogenesis, and metabolism, whereas benign tumors were enriched for cell morphogenesis, transmembrane ion transport, and immune regulation. PGK1 was the most significantly grade-related gene and increased expression of phosphoglycerate kinase 1 in GII and GIII tumors was confirmed by immunohistochemistry. Deconvolution of RNA-seq data revealed grade-related changes in the tumor microenvironment, notably a progressive decrease in border-associated macrophages from WHO GI to GIII tumors. Conclusions: In our study, we characterized key genes and processes dysregulated in high-grade meningiomas, including less understood mechanisms such as metabolic reprogramming, disrupted ion transport, altered immune regulation, and differences in the tumor microenvironment between benign and aggressive tumors.