In a recent study published in natureIn this study, the researchers attempted to investigate whether the functional connectivity between glioblastoma and the brain affects neural circuits regulating cognition and the survival of patients with high-grade glioblastoma.
Gliomas are interwoven into synaptic neural circuits. The authors previously showed that the infiltrating cortex of glioblastomas showed increased excitability of neurons, or gliomas that remodeled neural circuits in awake, willing patients.
However, the mechanisms by which glioblastomas interact with neural circuits in the human brain and alter cortical function remain unclear.
A better understanding of these processes could help find therapeutic targets for gliomas, the deadliest type of malignant brain tumor.
In this study, the researchers first examined short-term circuit dynamics using electrocardiography (ECoG) in 14 awake adult patients undergoing intraoperative brain mapping for surgical resection. This helped the researchers decipher neural responses and reveal biological drivers of synaptic enrichment in glioblastoma cells.
These patients had glioblastoma dominant in the cerebral hemisphere infiltrating speech production areas in the inferior frontal lobe of the cerebral cortex.
The team recruited the study population from a prospective registry of adults between the ages of 18 and 85 with high-grade gliomas. All were native English speakers and had no psychiatric/neurological illness or history of substance abuse.
Next, the team performed RNA sequencing (RNA-seq) and mouse xenograft experiments using the tumors of a subset of eight patients.
Another 19 patients provided samples for site-guided tumor biopsies, which the team used for immunofluorescence/immunohistochemistry analysis.
The tumors of another 24 patients were assisted by immunohistochemistry and cell-based functional assays. Overall, this multifaceted approach made it possible to study the clinical implications of glioma interactions with neurons.
Short-term ECoG analysis showed speech-specific activation and functional remodeling of language circuits, which promote glioma progression and impair cognition.
The high functional conductance (HFC) regions of glioblastoma comprise a molecularly distinct subpopulation that responds differently to neuronal signals, exhibiting a proliferative and invasive profile in nature.
Bulk transcriptome RNA-seq analysis revealed a seven-fold upregulation of thrombospondin-1 (THBS1), a gene involved in the assembly of neural circuits, in HFC tumor regions.
Within tumor regions of low functional connectivity (LFC), subpopulations of non-neoplastic astrocytes primarily drive THBS1 gene expression, whereas in HFC regions, high-grade glioma cells overexpress gene expression and, thus, promote neural circuit remodeling.
Although the exact role of TSP-1 in the tumor microenvironment (TME) is not clear, myeloid cell expression of TSP-1 indicates that multiple types of TME cells in HFC regions contribute to increased synaptic potential.
These findings are in good agreement with the principles of cancer biology that subpopulations play distinct roles within TME-heterogeneous cancers and that functional connectivity measures may partially define these roles.
Glioblastoma TME consists of bone marrow-derived macrophages, neutrophils, dendritic cells and microglia, and cell surface molecules, such as CD36 and CD47, that act as thrombospondin-1 (TSP-1) gene receptors.
Characterized regions within the tumor maintained functional connectivity by a subpopulation of glioma cells expressing the TSP-1 gene.
Kaplan-Meier survival analysis with a median follow-up time of 50.5 months showed an inverse relationship between patient survival and tumor functional connectivity.
Accordingly, patients with glioblastoma showed a functional tumor-brain connection and experienced a shorter overall survival compared with patients without HFC (71 weeks vs 123 weeks).
Administration of gabapentin (GBP) to mice bearing HFC-treated patient-derived xenografts (PDX) resulted in a significant reduction in glioma proliferation compared to vehicle-treated controls.
This finding highlights a potential therapeutic intervention for evaluation in clinical studies, which uses pharmacological inhibition of TSP-1 with the FDA-approved drug GBP to reduce glioblastoma cell proliferation and increase network synchronization within the TME.
Previous research has shown that neuronal activity promotes glioma proliferation through paracrine and synaptic signaling, influencing cognition and survival. In this study, the researchers demonstrated that glioblastoma remodels functional neuronal circuits, which negatively affects patient survival.
However, this finding does not establish a cause-and-effect relationship. It is possible that gliomas arising in functionally connected neural circuits may be more interconnected (functional).
Thus, they show higher glioma proliferation and reactivity in the network, which promotes HFC migration.
An in-depth understanding of the crosstalk between gliomas and healthy neurons and how their functional integration affects clinical manifestations could open doors to drug therapies and neuromodulators to improve cognition and patient survival.