Central nervous system regulation of diffuse glioma growth and invasion: from single unit physiology to circuit remodeling

Abstract

Purpose: Understanding the complex bidirectional interactions between neurons and glioma cells could help to identify new therapeutic targets. Herein, the techniques and application of novel neuroscience tools implemented to study the complex interactions between brain and malignant gliomas, their results, and the potential therapeutic opportunities were reviewed.

Methods: Literature search was performed on PubMed between 2001 and 2023 using the keywords "glioma", "glioblastoma", "circuit remodeling", "plasticity", "neuron networks" and "cortical networks". Studies including grade 2 to 4 gliomas, diffuse midline gliomas, and diffuse intrinsic pontine gliomas were considered.

Results: Glioma cells are connected through tumour microtubes and form a highly connected network within which pacemaker cells drive tumorigenesis. Unconnected cells have increased invasion capabilities. Glioma cells are also synaptically integrated within neural circuitry. Neurons promote tumour growth via paracrine and direct electrochemical mechanisms, including glutamatergic AMPA-receptors. Increased glutamate release in the tumor microenvironment and loss of peritumoral GABAergic inhibitory interneurons result in network hyperexcitability and secondary epilepsy. Functional imaging, local field potentials and subcortical mapping, performed in awake patients, have defined patterns of malignant circuit remodeling. Glioma-induced remodeling is frequent in language and even motor cortical networks, depending on tumour biological parameters, and influences functional outcomes.

Conclusion: These data offer new insights into glioma tumorigenesis. Future work will be needed to understand how tumor intrinsic molecular drivers influence neuron-glioma interactions but also to integrate these results to design new therapeutic options for patients.

Keywords: Cancer Neurosciences; Circuit Remodeling; Glioblastoma; Malignant glioma; Neuroplasticity.

Fig. 1

Simplified representation of the interactions between tumours cells and the bidirectional crosstalk between neurons and tumour cells (created with Biorender). A. Interactions between tumour cells. Tumor cells (green) form an extensive network, mediated by tumor microtubes that bear Connexin 43 gap-junctions, and are resistant to radio-chemotherapy. Within the network, pacemaker-like cells, thanks to KCa 3.1 channels (yellow), display rhythmic Ca²⁺ oscillations that are transmitted to the network and that drive tumour aggressiveness via activation of the MAPK and NF-κB pathways. Unconnected cells have increased invasion abilities. B. Neuronal activity-regulated tumour growth. First, neurons (purple) emit a paracrine signaling, notably mediated by BDNF and NLGN3, that stimulates tumour growth. NLGN3 is clived from neural cells by the ADAM10 sheddase. NLGN3 activates the PI3K-mTOR pathway and feedforwards its expression. Second, through excitatory glutamate neuro-gliomal synapses, whose establishment is eased by NLGN3, neurons activity stimulates tumors growth. BDNF binding to NTRK2 receptors increases the expression of AMPA receptors (red), which strengthen glutamate signaling. The neuron-dependent secretion of TSP1 by tumour cells contributes to tumour microtube formation and glioma progression. C. Glioma-induced neuronal activity modifications. Glutamate is released by glioma cells through the cystine/glutamate antiporter xc⁻ (brown). Peritumoral reactive astrocytes have a decreased capability to uptake glutamate. First, the increased glutamate rate in the tumour microenvironment induces neuronal hyperexcitability. Second, glutamate-toxicity leads to the death of fast-spiking GABAergic inhibitory neurons. Third, the drop in the neuronal expression of the potassium/chloride transporter KCC2 (dark red) is responsible for the switch from inhibitory to excitatory of GABA signaling. Fourth, the disruption of perineuronal nets by glioma-secreted matrix metalloproteinases amplifies the loss of GABAergic inhibition and glutamate-induced neuronal death

Fig. 2

Representation of the different tools offering the possibility to study glioma-induced malignant circuit remodeling as well as nervous system regulation of glioma proliferation and invasion at the macroscopic level (created with Biorender)