Multi-omics and Pharmacological Characterization of Patient-derived Glioma Cell Lines

Abstract

AbstractGlioblastoma (GBM) is the most common brain tumor and is currently incurable. Primary GBM cultures are widely used tools for screening potentially therapeutic drugs; however, there is a lack of genomic and pharmacological characterization of these primary GBM cultures. Here, we collected 52 patient-derived glioma cell (PDGC) lines and characterized them through whole- genome sequencing (WGS), RNA-seq, and drug response screening. We identified three molecular subtypes among PDGCs: mesenchymal (MES), proneural (PN), and oxidative phosphorylation (OXPHOS). Upon profiling the responses of PDGCs to 214 drugs, we found that the PN subtype PDGCs were sensitive to tyrosine kinase inhibitors, whereas the OXPHOS subtype PDGCs were sensitive to histone deacetylase inhibitors, oxidative phosphorylation inhibitors, and HMG-CoA reductase inhibitors. PN and OXPHOS subtype PDGCs stably formed tumorsin vivoupon intracranial transplantation into immunodeficient mice, while most MES subtype PDGCs were incapable of tumorigenesisin vivo. In addition, profiling and follow-up investigations showed that the serum-free culture system used for PDGCs enriched and propagated rareMYC/MYCN- amplified glioma cells. Our study provides a resource for understanding primary glioma cell cultures and aiding clinical translation.SignificanceOur study provides a resource for patient-derived glioma cell lines (PDGCs) on transcriptome, genome, drug response, and tumorigenic abilities. PDGCs are categorized into PN, MES, and OXPHOS subtypes, with MES-subtype PDGCs incapable of tumorigenesisin vivo. Notably, the serum-free culture system for PDGCs enriches glioma cells withMYC/MYCNamplification.