Synaptic proximity enables NMDAR signaling to promote brain metastasis

Metastasis - the disseminated growth of tumours in distant organs – underlies cancer mortality. Breast-to-brain metastasis (B2BM) is disconcertingly common and disruptive, being prevalent in the aggressive basal-like subtype, albeit evident at varying frequencies in all subtypes. Previous studies revealed parameters of breast cancer metastasis to brain, but its preference for this site remains an enigma. Herein we show that B2BM cells co-opt a neuronal signaling pathway recently implicated in invasive tumour growth, involving activation by glutamate ligand of an N-methyl-D-aspartate receptor (NMDAR), whose signaling is demonstrably instrumental in model systems for metastatic colonization of the brain, and associated with poor prognosis. While NMDAR receptor activation is autocrine in some primary tumour types, human and mouse B2BM cells express receptors but secrete insufficient glutamate to activate signaling, which is instead supplied via the formation of pseudo-tripartite synapses between cancer cells and glutamatergic neurons, presenting an insidious rationale for brain metastasis.