RT Journal Article
SR Electronic
T1 Targeting neuronal activity-regulated neuroligin-3 dependency for high-grade glioma therapy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 153122
DO 10.1101/153122
A1 Humsa S. Venkatesh
A1 Lydia T. Tam
A1 Pamelyn J. Woo
A1 Surya Nagaraja
A1 Shawn M. Gillespe
A1 James Lennon
A1 Jing Ni
A1 Damien Y. Duveau
A1 Patrick J. Morris
A1 Jean J. Zhao
A1 Craig J. Thomas
A1 Michelle Monje
YR 2017
UL http://biorxiv.org/content/early/2017/06/21/153122.abstract
AB 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.