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Glioblastoma remodeling of neural circuits in the human brain decreases survival

Saritha Krishna, View ORCID ProfileAbrar Choudhury, Kyounghee Seo, Lijun Ni, Sofia Kakaizada, Anthony Lee, Alexander Aabedi, Caroline Cao, Rasika Sudharshan, Andrew Egladyous, Nyle Almeida, Humsa S. Venkatesh, Anne Findlay, Srikantan Nagarajan, David Raleigh, David Brang, Michelle Monje, Shawn L. Hervey-Jumper
doi: https://doi.org/10.1101/2021.02.18.431915
Saritha Krishna
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
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Abrar Choudhury
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
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  • ORCID record for Abrar Choudhury
Kyounghee Seo
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
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Lijun Ni
2Department of Neurology, Stanford University, Stanford, CA, 94305, USA
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Sofia Kakaizada
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
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Anthony Lee
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
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Alexander Aabedi
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
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Caroline Cao
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
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Rasika Sudharshan
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
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Andrew Egladyous
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
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Nyle Almeida
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
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Humsa S. Venkatesh
2Department of Neurology, Stanford University, Stanford, CA, 94305, USA
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Anne Findlay
3Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, 94143, USA
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Srikantan Nagarajan
3Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, 94143, USA
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David Raleigh
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
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David Brang
4Department of Psychology, University of Michigan, Ann Arbor, MI, 48109, USA
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Michelle Monje
2Department of Neurology, Stanford University, Stanford, CA, 94305, USA
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Shawn L. Hervey-Jumper
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
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  • For correspondence: Shawn.Hervey-Jumper@ucsf.edu
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Summary

Gliomas synaptically integrate into neural circuits. Prior work has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth and gliomas increasing neuronal excitability. In this study we wanted to know how glioma induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. We use intracranial brain recordings during lexical retrieval language tasks in awake humans in addition to site specific tumor tissue biopsies and cell biology experiments. We find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumor-infiltrated cortex, beyond cortical excitation normally recruited in the healthy brain. Site-directed biopsies from functionally connected regions within the tumor are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumor cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumor regions compared to tumor regions with less functional connectivity. The degree of functional connectivity between glioblastoma and the normal brain negatively impacts both patient survival and language task performance. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumor proliferation and impairs cognition.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 19, 2021.
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Glioblastoma remodeling of neural circuits in the human brain decreases survival
Saritha Krishna, Abrar Choudhury, Kyounghee Seo, Lijun Ni, Sofia Kakaizada, Anthony Lee, Alexander Aabedi, Caroline Cao, Rasika Sudharshan, Andrew Egladyous, Nyle Almeida, Humsa S. Venkatesh, Anne Findlay, Srikantan Nagarajan, David Raleigh, David Brang, Michelle Monje, Shawn L. Hervey-Jumper
bioRxiv 2021.02.18.431915; doi: https://doi.org/10.1101/2021.02.18.431915
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Glioblastoma remodeling of neural circuits in the human brain decreases survival
Saritha Krishna, Abrar Choudhury, Kyounghee Seo, Lijun Ni, Sofia Kakaizada, Anthony Lee, Alexander Aabedi, Caroline Cao, Rasika Sudharshan, Andrew Egladyous, Nyle Almeida, Humsa S. Venkatesh, Anne Findlay, Srikantan Nagarajan, David Raleigh, David Brang, Michelle Monje, Shawn L. Hervey-Jumper
bioRxiv 2021.02.18.431915; doi: https://doi.org/10.1101/2021.02.18.431915

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