High-grade gliomas remodel neural circuits: promoting tumor progression and impaired cognition

By Neha MathurMay 9 2023Reviewed by Lily Ramsey, LLM

In a recent study published in Nature, researchers attempted to investigate whether functional connectivity between glioblastoma and the brain affected cognition-regulating neural circuits and the survival of patients with high-grade glioblastomas.

Study: Glioblastoma remodelling of human neural circuits decreases survival. Image Credit: Aprilstock/Shutterstock.com

Background

Gliomas integrate into neural circuits synaptically. The authors previously demonstrated that the glioblastoma-infiltrated cortex exhibited increased neuronal excitability, or gliomas remodeled neural circuits in awake, resting patients.

However, mechanisms by which glioblastomas engage with neuronal circuits in the human brain and change cortical function remain unclear.

A better understanding of these processes could help find therapeutic targets for gliomas, the most lethal type of malignant brain tumors.

About the study

In the present study, researchers first examined short-range circuit dynamics using electrocorticography (ECoG) in 14 adult awake patients undergoing intraoperative brain mapping for surgical resection. This helped the researchers decode neural responses and revealed biological drivers of synaptic enrichment in glioblastoma cells.

These patients had dominant hemisphere glioblastoma infiltrating speech production areas of the inferior frontal lobe of the brain cortex.

The team recruited the study population from a prospective registry of adults aged 18 to 85 with new-onset high-grade gliomas. All were native English-speaking individuals with no psychiatric/neurological illness or substance abuse history.

Next, the team conducted ribonucleic acid sequencing (RNA-seq) and mouse xenograft experiments using tumors of a subset of eight patients.

Another 19 patients provided samples for site-directed tumor biopsies, which the team used for immunofluorescence/immunohistochemistry analysis.

Tumors for another 24 patients helped conduct immunocytochemistry and cell-based functional assays. Overall, this multi-faceted approach enabled studying the clinical implications of glioma–neuron interactions.

Results

Short-range ECoG analysis demonstrated speech-specific activation and functional remodeling of language circuits, promoting glioma progression and damaging cognition.

High functional connectivity (HFC) regions of glioblastoma comprise a molecularly distinct glioma subpopulation that differentially responds to neuronal signals, exhibiting an inherently proliferative and invasive profile.

Bulk RNA-seq transcriptomic analysis revealed sevenfold upregulation of thrombospondin-1 (THBS1), a gene involved in the assembly of neural circuits, in HFC tumor regions.

Within low functional connectivity (LFC) tumor regions, a non-tumorous astrocyte cell subpopulation primarily drives THBS1 gene expression, whereas, within HFC regions, high-grade glioma cells express gene expression, thus, further promoting neural circuit remodeling.

Although the exact role of TSP-1 in the tumor microenvironment (TME) is unclear, myeloid cell expression of TSP-1 suggests that multiple types of TME cells in HFC regions contribute to a higher synaptogenic potential.  

These findings are well-aligned with the cancer biology principles that cell subpopulations take up distinct roles within the heterogenous cancer TME and functional connectivity measures could partially define these roles.

The glioblastoma TME comprises bone-marrow-derived macrophages, neutrophils, dendritic and microglial cells, and cell surface molecules, such as CD36 and CD47, which function as thrombospondin-1 (TSP-1) gene receptors.

The distinct intratumoral regions maintained functional connectivity through a glioma cell subpopulation expressing the TSP-1 gene.

A Kaplan–Meier survival analysis with a mean follow-up time of 50.5 months illustrated an inverse relationship between patient survival and functional connectivity of the tumor.

Accordingly, patients with glioblastoma displayed functional connectivity between the tumor and the brain experienced an overall survival of shorter duration compared to non-HFC patients (71 weeks vs. 123 weeks).

Gabapentin (GBP) administration to mice bearing HFC patient-derived xenografts (PDX) markedly decreased glioma proliferation relative to vehicle-treated controls.

This finding highlighted a potential therapeutic intervention for assessment in clinical studies, which employs pharmacological inhibition of TSP-1 using the FDA-approved drug GBP to decrease glioblastoma cell proliferation and augment network synchrony within the TME.

Conclusions

Previous research has shown that neuronal activity promotes glioma proliferation through paracrine and synaptic signaling, affecting cognition and survival. In this study, the researchers evidenced that glioblastomas remodel functional neural circuits, adversely influencing patient survival.

However, this finding does not establish a cause-and-effect relationship. It is feasible that gliomas originating in functionally connected neural circuits are more strongly (functionally) connected.

Thus, they exhibit higher glioma–network distribution & interaction, which encourages HFCs to migrate.

An in-depth understanding of the cross-talk between gliomas and healthy neurons and how their functional integration affects clinical manifestations could open doors for pharmacological therapies and neuromodulators for improving cognition and patient survival.