Glioblastoma remodelling of human neural circuits decreases survival

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.

Progress in cancer neuroscience

“…Additionally, it was noted that the extent of functional connectivity between a healthy brain and glioblastoma negatively affects individuals’ survival and language task outcomes. This investigation revealed that high‐grade GBMs functionally alter neural networks in the human brain, inducing tumor growth and cognition impairment 42 …”

“…Krishna et al 42 . carried out intraoperative electrophysiology analysis while the patients were engaged in language tasks, assessed glioblastoma‐infiltrated cortexs’ local field potentials during speech initiation, identified neural responses decodability, and indicated glioblastoma cells’ synaptic enrichment stimulators.…”

“…Briefly, they performed a short‐range electrocorticography assessment of the tumor‐infiltrated cortex to indicate language‐task‐specific functional remodeling and activation of language circuits. Furthermore, it was revealed that specific intratumoral regions maintained functional connectivity by thrombospondin/thrombin sensitive protein 1 (TSP‐1)‐expressing malignant cells subpopulation (high functional connectivity (HFC) GBM cells), suggesting that pharmacological suppression of TSP‐1 reduces glioblastoma cell growth and network synchrony in TME and highlighting an efficient therapeutic strategy for future clinical research 42 . Moreover, it was determined how GBM‐mediated neuronal alterations affected cognition‐associated neural circuits and if these interactions impacted individuals’ survival.…”

“…Some studies with a heterogeneous population of patients indicated that the overall survival was increased with functional connectivity 43–45 ; however, these data are largely affected by limited spatial resolution, tumor vascularity, and a heterogenous patient cohort. Nonetheless, Krishna et al 42 . need to address the direction of causality.…”

How can cancer research be illuminated by brain research (and vice versa)?

“…To begin with, childhood brain tumors appear to imitate embryonic brain development and have been described as "developmental processes gone awry," 2 while even adult brain tumors appear to influence the surrounding neurons, leading even to cognitive decline. 3 Moving forward, the overexpression of the now well-known BRAF (V600E) mutations in murine erythron-myeloid progenitor cells, which are precursors to microglia cells, clarified their role as the fetal cellular origin for histiocytosis (ie, a spectrum of myeloid diseases) but also revealed broader mechanisms of microglia-dependent neurodegeneration not necessarily limited to histiocytosis, such as the role of mitogen-activated protein kinase (MAPK) in this degeneration type. 4 In addition, systems biology in silico analyses have pointed out that oncogenes' and/or tumor suppressors genetic mutations are remarkably prevalent in neurodevelopmental and neurological diseases (eg, autism spectrum disorders), and the associated genes' expression levels are increased in both brain and other organs.…”