The Complex Molecular Epileptogenesis Landscape of Glioblastoma

Authors

Victoria Soeung
Ralph B Puchalski
Jeffrey L Noebels

Publication Date

8-20-2024

Journal

Cell Medicine Reports

DOI

10.1016/j.xcrm.2024.101691

PMID

39168100

PMCID

PMC11384957

PubMedCentral® Posted Date

8-20-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Glioblastoma, Humans, Brain Neoplasms, Epilepsy, Gene Expression Regulation, Neoplastic, Transcriptome, Tumor Microenvironment, spatial transcriptome, GBM, monogenic epilepsy, microenvironment, tumor margin, hyperexcitability, proliferation, focal dysplasia, autoimmune epilepsy, epistasis

Abstract

The cortical microenvironment surrounding malignant glioblastoma is a source of depolarizing crosstalk favoring hyperexcitability, tumor expansion, and immune evasion. Neosynaptogenesis, excess glutamate, and altered intrinsic membrane currents contribute to excitability dyshomeostasis, yet only half of the cases develop seizures, suggesting that tumor and host genomics, along with location, rather than mass effect, play a critical role. We analyzed the spatial contours and expression of 358 clinically validated human epilepsy genes in the human glioblastoma transcriptome compared to non-tumor adult and developing cortex datasets. Nearly half, including dosage-sensitive genes whose expression levels are securely linked to monogenic epilepsy, are strikingly enriched and aberrantly regulated at the leading edge, supporting a complex epistatic basis for peritumoral epileptogenesis. Surround hyperexcitability induced by complex patterns of proepileptic gene expression may explain the limited efficacy of narrowly targeted antiseizure medicines and the persistence of epilepsy following tumor resection and clarify why not all brain tumors provoke seizures.

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