Journal Article

Neuronal Cannabinoid CB1 Receptors Suppress the Growth of Melanoma Brain Metastases by Inhibiting Glutamatergic Signalling

Blázquez, Cristina, Costas-Insua, Carlos, Sánchez, Cristina, Sánchez-Laorden, Berta, Marsicano, Giovanni, Seijo-Vila, Marta, Pérez-Gómez, Eduardo, Guzmán, Manuel, Blasco-Benito, Sandra, Rodríguez-Baena, Francisco Javier

2023

Overview

Melanoma is one of the deadliest forms of cancer. Most melanoma deaths are caused by distant metastases in several organs, especially the brain, the so-called melanoma brain metastases (MBMs). However, the precise mechanisms that sustain the growth of MBMs remain elusive. Recently, the excitatory neurotransmitter glutamate has been proposed as a brain-specific, pro-tumorigenic signal for various types of cancers, but how neuronal glutamate shuttling onto metastases is regulated remains unknown. Here, we show that the cannabinoid CB1 receptor (CB1R), a master regulator of glutamate output from nerve terminals, controls MBM proliferation. First, in silico transcriptomic analysis of cancer-genome atlases indicated an aberrant expression of glutamate receptors in human metastatic melanoma samples. Second, in vitro experiments conducted on three different melanoma cell lines showed that the selective blockade of glutamatergic NMDA receptors, but not AMPA or metabotropic receptors, reduces cell proliferation. Third, in vivo grafting of melanoma cells in the brain of mice selectively devoid of CB1Rs in glutamatergic neurons increased tumour cell proliferation in concert with NMDA receptor activation, whereas melanoma cell growth in other tissue locations was not affected. Taken together, our findings demonstrate an unprecedented regulatory role of neuronal CB1Rs in the MBM tumour microenvironment.

• Publisher: MDPI AG,Taylor & Francis,MDPI
• Subject: Brain cancer / Brain tumors / Breast cancer / Cancer / Cannabinoid CB1 receptors / Cannabinoids / Cell activation / Cell growth / Cell proliferation / Genetic engineering / Genomes / Glutamatergic transmission / Glutamic acid receptors / Glutamic acid receptors (ionotropic) / Life Sciences / Melanoma / Metabotropic receptors / Metastases / Metastasis / Molecular modelling / Mortality / N-Methyl-D-aspartic acid receptors / Nerve endings / Neurons / Neurons and Cognition / Parenchyma / Penicillin / Receptor mechanisms / Transcriptomics / Tumor microenvironment / α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid