TY - JOUR T1 - Targeting neuronal activity-regulated neuroligin-3 dependency for high-grade glioma therapy JF - bioRxiv DO - 10.1101/153122 SP - 153122 AU - Humsa S. Venkatesh AU - Lydia T. Tam AU - Pamelyn J. Woo AU - Surya Nagaraja AU - Shawn M. Gillespe AU - James Lennon AU - Jing Ni AU - Damien Y. Duveau AU - Patrick J. Morris AU - Jean J. Zhao AU - Craig J. Thomas AU - Michelle Monje Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/06/21/153122.abstract N2 - Neuronal activity promotes high-grade glioma (HGG) growth. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule and glioma mitogen neuroligin-3 (Nlgn3), but the therapeutic potential of targeting Nlgn3 in glioma remains to be defined. We demonstrate a striking dependence of HGG growth on microenvironmental Nlgn3 and determine a targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric glioblastoma, diffuse intrinsic pontine glioma and adult glioblastoma fail to grow in Nlgn3 knockout mice. Glioma exposure to Nlgn3 results in numerous signaling consequences, including early focal adhesion kinase activation upstream of PI3K-mTOR. Nlgn3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. Administration of ADAM10 inhibitors robustly blocks HGG xenograft growth. This work defines the therapeutic potential of and a promising strategy for targeting Nlgn3 secretion in the glioma microenvironment, which could prove transformative for treatment of HGG. ER -