Molecular mechanisms and therapeutic targets in glioblastoma multiforme: network and single-cell analyses.

in Scientific reports by Xiangyu Chen, Xiao Zhong, Feifei Zhang, Xiaomei Zhou, Xiaofeng Yue, Xueru Li

TLDR

  • The study identified key genes and pathways involved in the tumor microenvironment of glioblastoma multiforme (GBM) and potential therapeutic targets, including the extracellular matrix and synaptic remodeling.
  • A 17-gene prognostic signature was developed to predict survival outcomes in GBM patients, and potential targeted therapies were identified using drug sensitivity analyses.

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor associated with poor survival outcomes and is driven by a complex tumor microenvironment (TME) that promotes tumor progression and treatment resistance. To explore the role of the TME in GBM, we analyzed glioma-related microarray and single-cell RNA sequencing (scRNA-seq) datasets from the Gene Expression Omnibus (GEO). Functional enrichment and weighted gene coexpression network analyses revealed distinct immune profiles, metabolic alterations, and differences in chemotherapeutic drug sensitivity between the high-risk and low-risk patient groups. scRNA-seq data processed with the 'Seurat' package were used to identify differentially expressed genes in pericytes, endothelial cells, and glioma cells, particularly those involved in extracellular matrix (ECM) remodeling. A 17-gene prognostic signature developed through Cox regression and LASSO analyses revealed that key genes (COL1A1, COL4A1, and VIM) were significantly associated with survival outcomes in GBM patients. Drug sensitivity analyses using data from the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) identified potential targeted therapies for GBM, including SB-505,124, staurosporine, and AZD8186. This integrative study underscores the critical roles of the ECM and synaptic remodeling in GBM and suggests novel therapeutic targets to improve personalized treatment strategies for GBM patients.

Overview

  • The study aimed to explore the role of the tumor microenvironment (TME) in glioblastoma multiforme (GBM) and identify potential therapeutic targets.
  • The researchers analyzed glioma-related microarray and single-cell RNA sequencing (scRNA-seq) datasets from the Gene Expression Omnibus (GEO).
  • The study aimed to identify key genes that are significantly associated with survival outcomes in GBM patients and potential targeted therapies for GBM.

Comparative Analysis & Findings

  • Functional enrichment and weighted gene coexpression network analyses revealed distinct immune profiles, metabolic alterations, and differences in chemotherapeutic drug sensitivity between high-risk and low-risk patient groups.
  • scRNA-seq data processing identified differentially expressed genes in pericytes, endothelial cells, and glioma cells, particularly those involved in extracellular matrix (ECM) remodeling.
  • A 17-gene prognostic signature developed through Cox regression and LASSO analyses revealed that key genes (COL1A1, COL4A1, and VIM) were significantly associated with survival outcomes in GBM patients.

Implications and Future Directions

  • The study underscores the critical roles of the ECM and synaptic remodeling in GBM and suggests novel therapeutic targets to improve personalized treatment strategies for GBM patients.
  • Future studies can explore the potential therapeutic applications of the identified genes and pathways in preclinical models and clinical trials.
  • The study highlights the importance of considering the TME in the development of targeted therapies for GBM, and future studies should investigate the interplay between GBM cells and the TME.
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