Abstract
Glioblastomas are invasive yet incurable brain tumors. Recent data have shown that glutamatergic neuron-to-glioma synapses drive glioblastoma proliferation and invasion. In this study, we set out to investigate whether glioblastoma could communicate with neurons via various neuron-derived neurotransmitters through a functional neurotransmitter receptor screening. For this purpose, we stably transduced glioblastoma cells with a genetically encoded calcium indicator and sequentially and locally applied eight different neurotransmitters to glioblastoma cells in neuron-glioma co-cultures. These neurotransmitters included acetylcholine, ATP, dopamine, glutamate, GABA, adrenaline, serotonin, and glycine. We observed functional responses to acetylcholine, glutamate, ATP, dopamine, indicating a potential role for diverse neuron-to-glioma communication. Further, we investigated in patient-derived xenograft models and human tissues the existence of putative neuron-to-glioma synapses that could signal via acetlycholine, ATP and dopamine. In conclusion, this study reveals that glioblastoma cells express a heterogeneous set of functional neurotransmitter receptors, which may facilitate neuron-to-tumor communication across broad neuronal populations and warrant further investigation into their role for tumor biology.