Tumor-associated epilepsy and high expression of xCT shape the proteome of IDH-wildtype glioblastoma

Given the role of glutamate signaling in glioma-associated epilepsy (GAE) and glioma cell growth, amino acid transporters have gained attention as therapeutic targets. Here, we conducted a comparative analysis of four key transporters-xCT, CD98, EAAT2, and ASCT1-with particular emphasis on xCT, due to the availability of clinically established inhibitors. Protein expression was quantified by immunoblot in snap-frozen tissue of tumor treatment-naïve IDH-mutant and IDH-wildtype gliomas (n = 87) with and without GAE. Quantitative whole-cell proteomics was performed on glioblastoma (GB) from 16 patients stratified for GAE and xCT expression levels. Gliomas from patients with GAE showed significantly higher EAAT2 and ASCT1 levels. In IDH-mutant versus IDH-wildtype glioma, xCT, EAAT2 and ASCT1 were significantly upregulated. Quantitative proteomics revealed 214 significantly regulated proteins in GB with GAE. Upregulated proteins showed enrichment for Gene Ontology (GO) terms involving neurotransmitter and amino acid turnover as well as lipid metabolism. Within the epilepsy group, xCT high-expressing tumors had distinct enrichment patterns. The 231 upregulated proteins partially overlapped with proteins upregulated in the epilepsy cohort, but additionally showed enrichment in pathways related to myelination and synaptic plasticity. In the survival analysis (n = 87), xCT expression and epilepsy did not affect patient survival in either IDH-mutant or IDH-wildtype tumors. Our findings highlight the role of amino acid transporters in GAE. The proteome analysis reveals distinct patterns in GB with epilepsy and also underscores the influence of xCT expression on the tumor proteome, which could inform the development of targeted anti-seizure medication.