Synaptic Communication in Brain Cancer

Abstract

Increasing evidence indicates that the nervous system plays a critical role in cancer progression. This is particularly true in cancers that occur within the central nervous system. Communication between neurons and cancer cells is a fundamental component of brain cancer pathophysiology, both for primary gliomas and for brain metastases. Neuronal activity drives growth of glial malignancies through secreted growth factors and through direct electrochemical synaptic communication. Reciprocally, brain cancers influence neuronal function, increasing neuronal activity and modulating the function of the circuits into which the cancer cells structurally and electrically integrate. Advancing understanding of neuron-cancer interactions will elucidate new therapeutic strategies for these presently lethal brain cancers.

Figure 1. Neuronal activity-regulated neuroligin-3 shedding drives glioma progression

Neuronal activity regulates the ADAM10-mediated cleavage and release of neuroligin-3 (red) from post-synaptic neurons and post-synaptic OPCs. The ectodomain of neuroligin-3 is shed (s-NLGN3) into the glioma microenvironment, where it binds to an as-of-yet unidentified binding partner on the glioma cell (green). NLGN3 binding activates focal adhesion kinase (FAK) and downstream SRC, RAS and PI3K-mTOR signaling pathways. NLGN3 binding also induces feed-forward expression of NLGN3 expression in a PI3K-mTOR-dependent manner. Together with upregulating its own expression in the glioma cell, NLGN3 increases expression of a number of synapse-related genes and promotes neuron-glioma synapse formation. Illustration by Sigrid Knemeyer at SciStories.