Abstract
The nervous system is implicated in pathology of both cranial and extracranial cancers. In glioblastoma, direct excitatory glutamatergic synapses between neurons and cancer cells were discovered. Importantly, these neuron-cancer contacts drive glioblastoma proliferation and invasion. However, such synapses have not yet been documented in other types of brain cancer. In the context of brain metastases, indirect, peri-synaptic contacts between breast cancer cells and neurons were observed, which promote brain metastatic growth through glutamatergic signaling via NMDA receptors on the neoplastic cells. Recently, two studies have demonstrated that neuronal activity supports the growth of both the primary tumor and brain metastases from neuroendocrine carcinoma small cell lung cancer. In the work presented here, we demonstrate direct neuron-cancer synapses in early-stage brain metastases originating from breast cancer and melanoma. These synapses exhibited the typical structural features observed in synaptic connections and induced postsynaptic currents in the cancer cells through the activation of AMPA subtype glutamate receptors. Importantly, genetic and pharmacological perturbation of these receptors reduces the number of brain metastases and the overall metastatic burden in preclinical models of breast cancer and melanoma. These results uncover a previously unknown form of direct communication between neurons and brain-metastatic breast cancer and melanoma tumor cells. This neuronal-tumor synaptic interaction demonstrates the significance of the neuronal microenvironment in the early stages of the brain metastatic cascade. Furthermore, it unveils a potential therapeutic vulnerability associated with the neuronal microenvironment, suggesting that targeting the synaptic communication between neurons and cancer cells could be a promising strategy to impede the progression of brain metastases.