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

Nature, 03 May 2023


Scientists use Axion’s Maestro MEA to examine the impact of high-grade gliomas on neural circuits in the human brain, investigate links to cognitive impairment, and discover a promising therapeutic avenue.  

Glioblastoma brain cancers are associated with cognitive impairment, but the underlying mechanisms are not fully understood. Building on previous research demonstrating that glioblastoma-neuronal crosstalk results in glioma growth and neural hyperexcitability, scientists in this study use a multiplatform approach including intracranial brain recordings and functional neuroimaging in glioblastoma patients, tumor biopsies, Maestro multielectrode array (MEA) analysis, and other methods to investigate the impact of glioma-induced changes in neural circuits related to cognition and examine links to patient survival.  

Task-associated neural function was assessed via electrocorticography in patients with glioblastoma, finding significantly increased activity in the high-gamma frequency band in tumor-infiltrated tissue compared to healthy tissue. Although task-relevant activity was preserved, neural activity was also detected in unexpected tumor-infiltrated cortical regions and the ability to decode complex word conditions was lost, suggesting glioma-induced remodeling of neural circuits. 

The scientists also discovered that a subpopulation of malignant cells within tumors with high functional connectivity (HFC) significantly upregulates synaptogenic genes that may contribute to circuit remodeling. Indeed, HFC biopsies co-cultured with mouse hippocampal neurons or integrated into hiPSC-derived neural organoids promoted increased synapse formation and glioma integration compared to low functional connectivity (LFC) biopsies. Exogenous TSP-1 addition to LFC organoids induced similar integration as the HFC organoids, suggesting TSP-1 involvement in synaptic remodeling and glioma integration. 

Functional activity of HFC and LFC glioma-cortical co-cultures was assessed with Axion’s noninvasive Maestro MEA system in real time, exhibiting increased network bursts and synchrony in the HFC co-cultures. In a preclinical xenograft model, HFC glioma tissue exhibited enhanced integration, tumor growth and progression, and reduced survival compared to LFC subpopulations. Clinically, after controlling for other survival factors, there is a strong inverse relationship between functional connectivity and survival. 

Finally, the Maestro was used to evaluate TSP-1 as a therapeutic target. Gabapentin treatment, which blocks the TSP-1 receptor, significantly reduced hyperexcitability and synchrony of HFC glioma-neuron co-cultures. Clinically, patient prognosis was also found to be worse with HFC tumors, and the authors suggest that targeting the mechanisms underlying glioma integration and synaptogenesis is a potentially promising therapeutic approach to treat glioblastoma.