Glioblastoma remodelling of human neural circuits decreases survival

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

Nature, 2023, vol. 617, issue 7961, 599-607

Abstract: Abstract Gliomas synaptically integrate into neural circuits1,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1–4 and gliomas increasing neuronal excitability2,5–8. 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.

Date: 2023
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DOI: 10.1038/s41586-023-06036-1

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