Integration of RNA-Seq and proteomics data identifies glioblastoma multiforme surfaceome signature

Abstract

Background Glioblastoma multiforme (GBM) is a highly lethal, stage IV brain tumour with a prevalence of approximately 2 per 10,000 people globally. The cell surface proteins or surfaceome serve as information gateway in many oncogenic signalling pathways and are important in modulating cancer phenotypes. Dysregulation in surfaceome expression and activity have been shown to promote tumorigenesis. The expression of GBM surfaceome is a case in point; OMICS screening in a cell-based system identified that this sub-proteome is largely perturbed in GBM. Additionally, since these cell surface proteins have ‘direct’ access to drugs, they are appealing targets for cancer therapy. However, a comprehensive GBM surfaceome landscape has not been fully defined yet. Thus, this study aimed to define GBM-associated surfaceome genes and identify key cell-surface genes that could potentially be developed as novel GBM biomarkers for therapeutic purposes. Methods We integrated the RNA-Seq data from TCGA GBM (n = 166) and GTEx normal brain cortex (n = 408) databases to identify the significantly dysregulated surfaceome in GBM. This was followed by an integrative analysis that combines transcriptomics, proteomics and protein-protein interaction network data to prioritize the high-confidence GBM surfaceome signature. Results Of the 2381 significantly dysregulated genes in GBM, 395 genes were classified as surfaceome. Via the integrative analysis, we identified 6 high-confidence GBM molecular signature, HLA-DRA, CD44, SLC1A5, EGFR, ITGB2, PTPRJ, which were significantly upregulated in GBM. The expression of these genes was validated in an independent transcriptomics database, which confirmed their upregulated expression in GBM. Importantly, high expression of CD44, PTPRJ and HLA-DRA is significantly associated with poor disease-free survival. Last, using the Drugbank database, we identified several clinically-approved drugs targeting the GBM molecular signature suggesting potential drug repurposing. Conclusions In summary, we identified and highlighted the key GBM surface-enriched repertoires that could be biologically relevant in supporting GBM pathogenesis. These genes could be further interrogated experimentally in future studies that could lead to efficient diagnostic/prognostic markers or potential treatment options for GBM.

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“…High-throughput technologies, including microarray gene expression and next-generation sequencing, are powerful and cost-effective technologies that provide the possibility for comprehensive identification and prioritization of GESPs with therapeutic potential in cancers. The major advantage of RNA-seq is providing the sequence of low abundance species and quantitative data, as the sequencing reads frequency represents the abundance of genes in the population 20 . However, the complex nature of biological systems, the lack of data availability, and the need for experimental validation can limit the effectiveness of bioinformatics approaches.…”

Recent Developments in Glioblastoma Therapy: Oncolytic Viruses and Emerging Future Strategies

“…Complex GB organoids (GBO) cultures were first gathered from multiple cell types derived from primary patient tumors to reflect their heterogenicity [ 227 ]. Neoplastic cerebral organoids (neoCOR) were developed via genetically manipulating cerebral organoids to induce GB growth [ 228 ]. Later, cerebral organoid GB co-cultures (GLICO) were generated from patient GSCs co-culturing with brain organoids to reflect the tumor–brain interactions [ 229 ].…”

Construction of Molecular Subtypes and Related Prognostic and Immune Response Models Based on M2 Macrophages in Glioblastoma

“…[49][50][51][52][53] FCGR2A, CYBB, CXCL8 and ITGB2 were significantly upregulated in GBM and associated with shorter overall survival of GBM patients. [54][55][56][57][58] As for the role of CCR1 in GBM, the results are still controversial. Zhang et al found that CCR1 and CCR5 were two key receptors of CCL8 and they triggered CCL8-induced invasion of GBM cells, 59 while Pham et al reported that individual deletion of CCR1 or CCR5 had little or no effect on the survival of tumor-bearing mice, or the number of GBM-infiltrated microglia/macrophages and lymphocytes.…”