Proneural and mesenchymal glioma stem cells display major differences in splicing and lncRNA profiles

Gabriela D A Guardia,Bruna R Correa,Patricia Rosa Araujo,Mei Qiao,Luiz O F Penalva,Suzanne Burns,Pedro A F Galante

doi:10.1038/s41525-019-0108-5

Abstract

Therapy resistance and recurrence in high-grade gliomas are driven by their populations of glioma stem cells (GSCs). Thus, detailed molecular characterization of GSCs is needed to develop more effective therapies. We conducted a study to identify differences in the splicing profile and expression of long non-coding RNAs in proneural and mesenchymal GSC cell lines. Genes related to cell cycle, DNA repair, cilium assembly, and splicing showed the most differences between GSC subgroups. We also identified genes distinctly associated with survival among patients of mesenchymal or proneural subgroups. We determined that multiple long non-coding RNAs with increased expression in mesenchymal GSCs are associated with poor survival of glioblastoma patients. In summary, our study established critical differences between proneural and mesenchymal GSCs in splicing profiles and expression of long non-coding RNA. These splicing isoforms and lncRNA signatures may contribute to the uniqueness of GSC subgroups, thus contributing to cancer phenotypes and explaining differences in therapeutic responses.

Highlights

High-grade (Grades III and IV) gliomas are the most common malignant brain tumors in adults
RNA-seq analysis revealed that MES and PN glioma stem cells (GSCs) showed differences in 4934 splicing events affecting 3253 genes (|ΔPSI| > 0.1 and false discovery rate [FDR] < 0.05, likelihood-ratio test); among these, 1793 events were not reported in the reference transcriptome (GENCODE version 26; Supplementary Table 2)
MES and PN GSCs showed a similar number of genes presenting alternative splicing (AS) events of exon skipping (ES), mutually exclusive exons (MXE), intron retention (IR), and alternative 5′/3′ splice sites (ASS; Fig. 1b)

Summary

Introduction

High-grade (Grades III and IV) gliomas are the most common malignant brain tumors in adults. Glioblastoma (GBM, grade IV) in particular is highly invasive and refractory to conventional therapy; GBM patients have an average survival of 15 months.[1] Therapy resistance and relapse are driven by glioma stem cells (GSCs), which comprise a small subpopulation of tumorigenic cells displaying stem-like properties: self-renewal, persistent proliferation, and ability to generate progeny of multiple lineages.[2]. Characterization of their biological properties, expression profile, and regulation is critical for creating new therapeutic strategies. Two explanations for this change have been proposed: (i) PN-MES transition, in which PN GSCs are triggered to switch to a MES phenotype upon treatment; and (ii) tumor heterogeneity: MES

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Conclusion