High-grade gliomas (HGG) are a devastating group of cancers, and represent the leading cause of brain tumour-related death in both children and adults. Therapies aimed at mechanisms intrinsic to glioma cells have translated to only limited success; effective therapeutic strategies will need also to target elements of the tumour microenvironment that promote glioma progression. Neuronal activity promotes the growth of a range of molecularly and clinically distinct HGG types, including adult and paediatric glioblastoma (GBM), anaplastic oligodendroglioma, and diffuse intrinsic pontine glioma (DIPG)1. An important mechanism that mediates this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic adhesion molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K–mTOR pathway1. However, the necessity of NLGN3 for glioma growth, the proteolytic mechanism of NLGN3 secretion, and the further molecular consequences of NLGN3 secretion in glioma cells remain unknown. Here we show that HGG growth depends on microenvironmental NLGN3, identify signalling cascades downstream of NLGN3 binding in glioma, and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of paediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. 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. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent the release of NLGN3 into the tumour microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting NLGN3 secretion, which could prove transformative for HGG therapy.
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The authors gratefully acknowledge support from the V Foundation, Liwei Wang Research Fund, National Institutes of Health (NINDS R01NS092597; NCI 1F31CA200273, P50 CA168504, P50 CA165962, R35 CA210057), Department of Defense (W81XWH-151-0131), McKenna Claire Foundation, Alex’s Lemonade Stand Foundation, The Cure Starts Now Foundation and DIPG Collaborative, Lyla Nsouli Foundation, Unravel Pediatric Cancer, California Institute for Regenerative Medicine (RN3-06510), Childhood Brain Tumor Foundation, Matthew Larson Foundation, the Joey Fabus Childhood Cancer Foundation, the Wayland Villars DIPG Foundation, the Connor Johnson, Zoey Ganesh, and Declan Gloster Memorial Funds, N8 Foundation, Virginia and D.K. Ludwig Fund for Cancer Research, Child Health Research Institute at Stanford Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases, and Breast Cancer Research Foundation and the intramural programs of the National Center for Advancing Translational Sciences and the National Cancer Institute.
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Invasion of white matter tracts by glioma stem cells is regulated by a NOTCH1–SOX2 positive-feedback loop
Nature Neuroscience (2019)