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


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Título :
Neuronal Cannabinoid CB1 Receptors Suppress the Growth of Melanoma Brain Metastases by Inhibiting Glutamatergic Signalling
Autor :
Costas-Insua, Carlos  
Seijo-Vila, Marta  
Blazquez, Cristina
Blasco Benito, Sandra  
Rodríguez Baena, Francisco Javier  
Marsicano, Giovanni  
Pérez-Gómez, Eduardo
Sánchez, Cristina
Sanchez-Laorden, Berta  
Guzmán, Manuel  
Editor :
Sanjay. K. Srivasta
Fecha de publicación:
2023-04-24
URI :
https://hdl.handle.net/11000/30783
Resumen :
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.
Palabras clave/Materias:
cannabinoid receptor
endocannabinoid system
melanoma
brain metastasis
glutamate
NMDA receptor
cell proliferation
Tipo documento :
application/pdf
Derechos de acceso:
info:eu-repo/semantics/openAccess
DOI :
https://doi.org/10.3390/cancers15092439
Aparece en las colecciones:
Instituto de Neurociencias



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