Single-cell RNA sequencing, SnATAC-seq, Glioblastoma, Mesenchymal, Therapeutic drugs, Transcription factor, Biotechnology, TP248.13-248.65, Biology (General), QH301-705.5, Biochemistry, QD415-436

Abstract The inherent heterogeneity of tumor cells impedes the development of targeted therapies for specific glioblastoma (GBM) subtypes. This study aims to investigate the mesenchymal subtype of GBM to uncover detailed characteristics, potential therapeutic strategies, and improve precision treatment for GBM patients. We integrated single-cell RNA sequencing (scRNA-seq), single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), and bulk RNA sequencing datasets to identify core gene modules, candidate therapeutic drugs, and key transcription factors specific to mesenchymal subtype GBM tumor cells which we validated in vitro and human samples. Our analysis encompassed a heterogeneous single-cell landscape of 55,845 cells from tumor and adjacent normal tissues, focusing on the mesenchymal subtype’s adverse prognosis and its association with hypoxia. We identified a core gene module composed of 38 genes and, through pharmacogenomic analysis, found that Trametinib and Dasatinib exhibit increased effectiveness against mesenchymal subtype GBM cells. Furthermore, by incorporating snATAC-seq data, we delineated a crucial regulatory network and pinpointed the key transcription factor CEBPG. Our research has highlighted the strong link between the mesenchymal-like (MES-like) properties of GBM and hypoxia, providing valuable insights into candidate drugs and pivotal targets for precision treatment of the mesenchymal subtype. Graphical Abstract