Neuroligin-3 and brain cancer

NLGN3 (neuroligin 3) is a mitogen/synaptic protein that promotes glioma proliferation through the PI3K–mTOR pathway. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K–mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. The tumors, called high-grade gliomas (HGG), are a group of deadly brain cancers that include adult glioblastoma, anaplastic oligodendroglioma, pediatric glioblastoma (GBM) and pediatric diffuse intrinsic pontine glioma (DIPG) [1]. Recent research in Stanford University found  that interrupting the neuroligin-3 signal could be a helpful strategy for controlling high-grade gliomas in human patients.  Neuroligin-3 activates multiple cancer promoting signaling pathways and increases the expression of genes involved in cell proliferation, promotion of malignancy, function of potassium channels and synapse function [2]. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors block the release of NLGN3 into the tumor microenvironment and robustly pause HGG xenograft growth [3]. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth [4]. Recent research suggests that interrupting the neuroligin-3 signal could be a helpful strategy for controlling high-grade gliomas in human patients. Using mice with normal neuroligin-3 brain signaling and human high-grade gliomas, the researchers tested whether two inhibitors of neuroligin-3 secretion could stop the cancers’ growth. One of the inhibitors has never been tested in humans, but the other has already reached phase-2 clinical trials as a potential chemotherapy for other forms of cancer outside the brain.

References:

1. http://www.nature.com/nature/journal/vaop/ncurrent/full/nature24014.html
2. http://med.stanford.edu/news/all-news/2017/09/brain-cancer-growth-halted-by-absence-of-protein.html
3. https://www.biorxiv.org/content/early/2017/06/21/153122
4. https://www.ncbi.nlm.nih.gov/pubmed/25913192