RT Journal Article
SR Electronic
T1 Glioblastoma remodeling of neural circuits in the human brain decreases survival
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.18.431915
DO 10.1101/2021.02.18.431915
A1 Saritha Krishna
A1 Abrar Choudhury
A1 Kyounghee Seo
A1 Lijun Ni
A1 Sofia Kakaizada
A1 Anthony Lee
A1 Alexander Aabedi
A1 Caroline Cao
A1 Rasika Sudharshan
A1 Andrew Egladyous
A1 Nyle Almeida
A1 Humsa S. Venkatesh
A1 Anne Findlay
A1 Srikantan Nagarajan
A1 David Raleigh
A1 David Brang
A1 Michelle Monje
A1 Shawn L. Hervey-Jumper
YR 2021
UL http://biorxiv.org/content/early/2021/02/19/2021.02.18.431915.abstract
AB 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 StatementThe authors have declared no competing interest.