Glioblastoma Rewires Neural Circuits That Impair Cognition and Survival

Within malignant brain tumors such as glioblastomas and other high-grade gliomas, neurons and tumor cells can interact and communicate through neuron–glioma synapses. Recent studies have demonstrated that neuronal activity can promote glioma progression, with gliomas increasing neuronal excitability at rest. To investigate how neuronal changes within the tumor-infiltrated cortex may alter cognitive task–specific neuronal function, Krishna and colleagues studied patients with dominant hemisphere glioblastomas and measured neuronal activity during auditory and visual picture naming tasks. Analysis of local neuronal activity via electrocorticography recordings of tumor-infiltrated or normal-appearing regions within the posterior lateral frontal cortex revealed that task-relevant neural activity was induced within the entire region of the tumor-infiltrated cortex, involved regions typically not involved in speech production, and was higher in tumor-infiltrated regions than matched normal-appearing cortex. Transcriptomic analyses of biopsy samples from tumor regions of high (HFC) or low functional connectivity (LFC) identified a population of glioma cells within HFC regions that highly express the synaptogenic factor thrombospondin-1 (TSP-1), encoded by THBS1. Coculture of induced human neuronal organoids with glioma cells isolated from HFC or LFC tumor regions demonstrated that HFC glioma cells integrated extensively in the organoids, whereas LFC cells did not, and exogenous TSP-1 was sufficient to induce LFC glioma–neuron interactions, supporting the role of TSP-1 in synapse formation. Moreover, HFC cells were particularly responsive to neuronal factors, as coculture with neurons or exposure to neuronal-conditioned medium specifically increased the proliferation rate and tumor microtube formation of HFC cells, and implantation of HFC glioma xenografts into the mouse hippocampus led to greater tumor burden and shorter survival compared with LFC xenografts. Survival analysis of patients with newly diagnosed glioblastoma indicated that a higher degree of intratumoral functional connectivity was associated with poor overall survival and reduced language cognitive performance. Together, these findings uncover how glioblastoma cells rewire cognitive neural circuitry to promote tumor progression and highlight the potential of agents such as gabapentin to reduce TSP-1–driven remodeling.

Krishna S, Choudhury A, Keough MB, Seo K, Ni L, Kakaizada S, et al. Glioblastoma remodelling of human neural circuits decreases survival. Nature 2023;617:599–607.

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