Glioblastoma remodeling of neural circuits in the human brain decreases survival

Abstract

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.

BOLD Coupling between Lesioned and Healthy Brain Is Associated with Glioma Patients’ Recovery

“…A growing literature is revealing that gliomas not only disrupt the tissue immediately surrounding the tumour but also exert long-range influences on distant brain areas [ 44 , 45 , 46 ]. Understanding how brain tumours integrate within brain circuits is crucial for prognoses.…”

“…Accordingly, glioblastoma patients present functionally connected voxels within the tumour mass, although with reduced connectivity strength when compared with HCs [ 25 ]. A recent study has found that functionally connected regions within a tumour are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neurotrophic phenotype [ 46 ]. Although BOLD fMRI has been successfully exploited to quantify tumour oxygenation [ 68 ], microvascular components [ 68 ], tumour delineation [ 20 ] and vascular disruption [ 69 ], interpreting a BOLD signal from tumour and lesioned tissue can be challenging.…”

“…There is recent evidence in support of the impact that glioma–brain interactions have on cognition. Patients with gliomas functionally connected with the rest of the brain according to MEG had lower scores in auditory and picture naming tasks [ 46 ]. Despite this promising evidence, the clinical benefit for patients is still very limited.…”

Lesion covariance networks reveal proposed origins and pathways of diffuse gliomas

“…Moreover, in addition to possessing the strongest correspondence to brain connectivity, LCN1 was also enriched with genes involved in neuronal processes such as synaptic signaling and synapse formation. A recent study illustrated that glioma cells enriched with these types of genes integrate into neural circuits involved in lexical processing, and that this neural integration supports tumor proliferation (Krishna et al, 2021). The genomic signature of a glioma may thus be an important predictor of the tumor's eventual migration patterns.…”

Functional alterations in cortical processing of speech in glioma-infiltrated cortex

“…Gliomas are the most common intrinsic brain tumors and a leading cause of neurological impairment in adults. Mounting evidence suggests that malignant gliomas remodel functional neuronal networks, and that these cellular-and network-level interactions impact cognition and survival (1). The mechanistic underpinnings of gliomaneuron interactions and their influence on human cognition is incompletely understood.…”