Glioblastoma–neuron networks

Abstract

Glioma cells can receive synaptic input from neurons, yet the spatial extent and diversity of synapse types of the neuron–glioma connectome remain unclear. In a recent paper in Cell, Tetzlaff, Reyhan and colleagues used a modified rabies-virus-based retrograde tracing approach to visualize neuron–tumor networks in patient-derived glioblastoma spheroid cultures, which were either co-cultured with human organotypic brain slices or xenografted into mouse brain. Live imaging revealed that functional connectivity between neurons and tumors occurred within hours in the co-cultures and within days in the xenograft models. Tumor-connected neurons appeared normal across multiple electrophysiological and morphological measures. The invasivity scores of individual tumors (derived from single-cell RNA-sequencing data) correlated with their ability to form synapses. The xenografts received brain-wide long-range projections, including from the contralateral hemisphere, as well as local projections near the site of engraftment. These inputs included glutamatergic, cholinergic and GABAergic neurons. The engrafted tumor exhibited muscarinic-dependent Ca²⁺ responses to acetylcholine, and knocking down the muscarinic acetylcholine receptor M3 in glioblastoma cells reduced xenografted tumor growth. Together, these data add to growing evidence of complex interactions between brain tumors and neuronal networks.

Original reference: Cell https://doi.org/10.1016/j.cell.2024.11.002 (2024)