Regulation of tumor proliferation by unlocking silent synapses on metastatic cancer cells

Abstract Several studies have revealed deleterious synapse formation onto cancer cells within the brain tumor microenvironment, yet these synapses are ∼100-fold weaker in presynaptic release rates and postsynaptic strength relative to bona fide synapses formed between neurons. Here, we find that most of the functional synapses on tumor cells are kept dormant and can be unlocked by overcoming GABA B receptor-mediated metabotropic signaling in neurons. Scavenging G βγ signaling in neurons increased presynaptic release probability on tumor cells and augmented cancer cell proliferation. Optical analysis of the tumor microenvironment revealed regulated secretion of neurotransmitters from tumor cells in response to GABA B receptor inhibition or electrical stimulation. These results reveal how cancer cells with a high propensity for brain metastasis leverage precise moments of aberrant excitation between neurons to engage reciprocal interactions that ultimately fuel cancer proliferation.