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

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 noncoding 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.

Decreased Equilibrative Nucleoside Transporter 1 (ENT1) Activity Contributes to the High Extracellular Adenosine Levels in Mesenchymal Glioblastoma Stem-Like Cells

“…The therapy resistance and relapse presented by the glioblastoma (GBM) are driven by glioma stem cells (GSCs) [ 38 ]. In recent years GSCs have been categorized based on their molecular and phenotypic differences in mesenchymal (MES) GSCs that have higher rates of proliferation in vitro and are more resistant to radiation than proneural (PN) GSCs [ 10 , 16 ].…”

“…In recent years GSCs have been categorized based on their molecular and phenotypic differences in mesenchymal (MES) GSCs that have higher rates of proliferation in vitro and are more resistant to radiation than proneural (PN) GSCs [ 10 , 16 ]. Primary PN GBM, originally responsive to treatment, may relapse as MES tumors which become refractory to treatment [ 38 ]. Thus, understanding the properties of both GSC subpopulations is clinically relevant for the management of patients.…”

Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide

“…Glioblastoma (GBM) is a fatal disease that can occur at any age, with a worse prognosis in older patients. The disease is considered to be driven by glioblastoma stem cells (GSCs), a small subpopulation of highly tumorigenic cells that have stem-like properties including self-renewal, high proliferation rates, and an ability to generate and regenerate different progenies of the tumor [ 1 , 2 , 3 , 4 , 5 ]. GSCs also regulate the molecular process of epithelial-like-to-mesenchymal-like transition (EMT) process, in which the cells acquire a greater motile and therapy resistant phenotype [ 6 ].…”

Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance

“…Of all GBMs, mesenchymal GSCs have the highest proliferative ability and poorest prognosis [23]. In the recent literature, mutated PTEN and NF1 can be viewed as molecular signatures of mesenchymal GBMs [24]. From in silico data, KDELC2 overexpression had a relatively high tendency of mesenchymal GBMs.…”