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Review
. 2022 Oct;19(6):1832-1843.
doi: 10.1007/s13311-022-01320-w. Epub 2022 Nov 10.

Brain Tumor Networks in Diffuse Glioma

Yvonne Yang #  1   2 , Marc C Schubert #  1   2   3 , Thomas Kuner  3 , Wolfgang Wick  1   2 , Frank Winkler  1   2 , Varun Venkataramani  4   5   6
Affiliations
Review

Brain Tumor Networks in Diffuse Glioma

Yvonne Yang et al. Neurotherapeutics. 2022 Oct.

Abstract

Diffuse gliomas are primary brain tumors associated with a poor prognosis. Cellular and molecular mechanisms driving the invasive growth patterns and therapeutic resistance are incompletely understood. The emerging field of cancer neuroscience offers a novel approach to study these brain tumors in the context of their intricate interactions with the nervous system employing and combining methodological toolsets from neuroscience and oncology. Increasing evidence has shown how neurodevelopmental and neuronal-like mechanisms are hijacked leading to the discovery of multicellular brain tumor networks. Here, we review how gap junction-coupled tumor-tumor-astrocyte networks, as well as synaptic and paracrine neuron-tumor networks drive glioma progression. Molecular mechanisms of these malignant, homo- and heterotypic networks, and their complex interplay are reviewed. Lastly, potential clinical-translational implications and resulting therapeutic strategies are discussed.

Keywords: Cancer neuroscience; Diffuse glioma; Glioblastoma; Neuron-glioma synapse; Neuron-tumor networks; Tumor-tumor networks.

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Figures

Fig. 1
Fig. 1
Tumor-tumor networks—molecular driver and biological function. Glioma cells are interconnected via TMs (glioma cells in violet) and integrate themselves into the astrocyte network (astrocytes in grey) to form a therapy resistant glioma cell network, communicating via gap junctions (red). Through gap junctions consisting of connexin 43, they can exchange small molecules (Ca2+, ATP) and toxic metabolites to regulate cellular homeostasis
Fig. 2
Fig. 2
Neuron-glioma networks molecular mechanisms and biological functions. Neuron-tumor communication is based on synaptic and paracrine pathways. Glutamatergic neuron-glioma synapse communication is mediated via AMPARs. EPSC excitatory postsynaptic currents, SIC slow inward currents. Perisynaptic glioma cell mediates synaptic transmission of physiological synapses, but their function is yet unclear. Paracrine signaling via NLGN-3, BDNF, IGF-1, COL1A2, and TSP-1 mediates paracrine neuron-to-tumor signaling. Neuronal input drives tumor cell invasion, TM growth, new formations of synapses, proliferation, progression, and tumor initiation
Fig. 3
Fig. 3
Glioma cells hijack neuronal-like mechanisms for cell invasion. By integrating transcriptomic signatures, cellular behavior, localization, and cell connectivity, two poles of cell states can be identified. Molecular signature of the neuronal-like subtype shows distinct characteristics in transcriptomic based classifications: NEU/NPC/OPC/Neurodevelopmental/high invasivity score. These cells are primarily unconnectedTUM/AC, highly invasive and to be found at the tumor rim. Network-integrated connectedTUM/AC cells in the tumor core, in contrast, form a tumor-tumor-astrocyte network and show transcriptomic signatures of AC-like/MES-like/Injury/low Invasity score
Fig. 4
Fig. 4
Neuronal hyperexcitability and remodeling. Bidirectional communication between neurons (blue) and glioma cells (violet) constructs a vicious circle leading to neuronal hyperexcitability (yellow). Reciprocal influence between glioma cells and neurons can lead to remodeling of both glioma cell and neuronal network
See this image and copyright information in PMC

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