Glioblastoma stem cells express non‐canonical proteins and exclusive mesenchymal‐like or non‐mesenchymal‐like protein signatures

Abstract

Glioblastoma (GBM) cancer stem cells (GSCs) contribute to GBM's origin, recurrence, and resistance to treatment. However, the understanding of how mRNA expression patterns of GBM subtypes are reflected at global proteome level in GSCs is limited. To characterize protein expression in GSCs, we performed in-depth proteogenomic analysis of patient-derived GSCs by RNA-sequencing and mass-spectrometry. We quantified > 10 000 proteins in two independent GSC panels and propose a GSC-associated proteomic signature characterizing two distinct phenotypic conditions; one defined by proteins upregulated in proneural and classical GSCs (GPClike), and another by proteins upregulated in mesenchymal GSCs (GMlike). The GM-like protein set in GBM tissue was associated with necrosis, recurrence, and worse overall survival. Through proteogenomics, we discovered 252 non-canonical peptides in the GSCs, i.e., protein sequences that are variant or derive from genome regions previously considered nonprotein-coding, including variants of the heterogeneous ribonucleoproteins implicated in RNA splicing. In summary, GSCs express two protein sets that have an inverse association with clinical outcomes in GBM. The discovery of non-canonical protein sequences questions existing gene models and pinpoints new protein targets for research in GBM.

The role of APOBEC3C in modulating the tumor microenvironment and stemness properties of glioma: evidence from pancancer analysis

“…However, the three primary factors of significance are GSCs, tumor heterogeneity, and the blood-brain barrier ( 63 ). Specifically, GSCs play a crucial role in tumor heterogeneity, as well as in the development of radio-resistance, chemo-resistance, and recurrence in GBM ( 64 ). In the glioma microenvironment, GSCs secrete cytokines that promote tumor invasion, immune cell recruitment, angiogenesis, and self-renewal, thereby contributing to cancer progression and recurrence ( 65 ).…”