Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Abstract

Summary High-grade gliomas (HGG) are a devastating group of cancers, representing the leading cause of brain tumor-related death in both children and adults. Therapies aimed at mechanisms intrinsic to the glioma cell have translated to only limited success; effective therapeutic strategies will need to also target elements of the tumor microenvironment that promote glioma progression. We recently demonstrated that neuronal activity robustly promotes the growth of a range of molecularly and clinically distinct HGG types, including adult glioblastoma (GBM), anaplastic oligodendroglioma, pediatric GBM, and diffuse intrinsic pontine glioma (DIPG)1. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway1. However, neuroligin-3 necessity to glioma growth, proteolytic mechanism of secretion and further molecular consequences in glioma remain to be clarified. Here, we demonstrate a striking dependence of HGG growth on microenvironmental neuroligin-3, elucidate signaling cascades downstream of neuroligin-3 binding in glioma and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. Neuroligin-3 stimulates numerous oncogenic pathways, including early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes including upregulation of numerous synapse-related genes in glioma cells. Neuroligin-3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent release of neuroligin-3 into the tumor microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting neuroligin-3 secretion, which could prove transformative for HGG therapy.

Glioblastoma recurrence correlates with NLGN3 levels

“…In the Figure I,J, we found that the level of NLGN3 was higher in the fundus region of GBM tissue compared to that in the surface region. Previous studies have shown that NLGN3 promotes the proliferation of gliomas by activating the PI3K‐mTOR pathway . Therefore, we further tested the level of p‐AKT (S473) in the GBM tissue and found that the level of p‐AKT (S473) was higher in the fundus region (Figure K,L).…”

“…Furthermore, in Figure we noticed that GBM would grow to deeper brain regions over time after its recurrence. Previous studies have demonstrated that microenvironmental NLGN3 is essential for the growth of GBM . Therefore, we hypothesized that NLGN3 plays an important role in the recurrence of GBM.…”

Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage

“…The lack of FMRP in Fmr1 KO mice leads to enhanced synaptic targeting of NLGN1 and NLGN3. Synaptic stimulation provokes very rapid proteolytic cleavage of NLGN1 and NLGN3 at both WT and Fmr1 KO synapses and reported to serve as the mitogen promoting glioma growth [70,71]. NLGN1 and NLGN3 cleavage was also suggested by the proteomics study [69] and there is a report regarding NLGN2 cleavage in Drosophila [72].…”

“…However, we reckon that more detailed analysis is required to understand the molecular mechanism of activity-dependent NLGNs shedding at the synapse and its consequences for synaptic functions. To date, two specific secretory proteases were proposed to cleave NLGN1: matrix metalloproteinase 9 (MMP-9) [52] and disintegrin and metalloproteinase domain-containing protein 10 (ADAM-10) [53,[69][70][71]. Recently, the cleaved NLGN3 was detected in the medium from optogenetically stimulated acute cortical slices WT Fmr1 KO Fig.…”

CA10 and CA11 negatively regulate neuronal activity‐dependent growth of gliomas

“…A recent study reveals that neurons could promote glioma growth through activity‐dependent secretion of neurotrophins, especially neuroligin‐3 (Venkatesh et al ., ). In addition, blocking neuroligin‐3 secretion by ADAM metallopeptidase domain 10 inhibitor shows a strong inhibition on the in vivo growth of gliomas (Venkatesh et al ., ). These studies highlight a crucial role of neuronal regulation on the aggression of gliomas and suggest that neuron‐derived neurotrophins are potential therapeutic targets for the treatment of gliomas (Johung and Monje, ).…”