Journal Article

Glioblastoma remodelling of human neural circuits decreases survival

Zhang, Yalan, Kakaizada, Sofia, Choudhury, Abrar, Popova, Galina, Nagarajan, Srikantan, Ni, Lijun, Egladyous, Andrew, Hyer, Jeanette, Chang, Edward F., Lipkin, Benjamin, Phillips, Joanna J., Brang, David, Cao, Caroline, Almeida, Nyle, Molinaro, Annette M., Lee, Anthony, Keough, Michael B., Shamardani, Kiarash, Monje, Michelle, Daniel, Andy G. S., Raleigh, David R., Hervey-Jumper, Shawn L., Aabedi, Alexander, Nava Gonzales, Cesar, Venkatesh, Humsa S., Seo, Kyounghee, Findlay, Anne, Sudharshan, Rasika, Krishna, Saritha

2023

Overview

Gliomas synaptically integrate into neural circuits 1 , 2 . Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth 1 – 4 and gliomas increasing neuronal excitability 2 , 5 – 8 . Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron–glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition. High-grade gliomas functionally remodel neural circuits in the human brain, promoting tumour progression and impairing cognition.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 13 / 13/1 / 13/106 / 13/109 / 13/51 / 14 / 14/1 / 14/19 / 14/28 / 14/63 / 38 / 38/91 / 42 / 42/41 / 59 / 59/57 / 631/378/3920 / 631/67/1922 / 631/67/327 / 64 / 64/60 / 82 / 82/51 / 96 / 96/106 / Biopsy / Brain / Brain - drug effects / Brain - metabolism / Brain - pathology / Brain cancer / Brain Neoplasms - drug therapy / Brain Neoplasms - metabolism / Brain Neoplasms - pathology / Brain tumors / Cell Proliferation - drug effects / Circuits / Cognition / Cognition & reasoning / Disease Progression / Gabapentin / Gabapentin - pharmacology / Gabapentin - therapeutic use / Glioblastoma / Glioblastoma - drug therapy / Glioblastoma - metabolism / Glioblastoma - pathology / Glioma / Glioma cells / Humanities and Social Sciences / Humans / Language / multidisciplinary / Neural networks / Neural Pathways / Neurons / Patients / Phenotypes / Science / Science (multidisciplinary) / Speech / Survival / Survival Rate / Thrombospondin / Thrombospondin 1 - antagonists & inhibitors / Tumors / Wakefulness