DIPG-21. ELECTRICAL INTEGRATION OF GLIOMA INTO NEURAL CIRCUITRY. (23rd April 2019)

• Record Type: Journal Article
• Authors: Venkatesh, Humsa; Morishita, Wade; Geraghty, Anna; Silverbush, Dana; Arzt, Marlene; Tam, Lydia; Ponnuswami, Anitha; Gillespie, Shawn; Agarwal, Amit; Regev, Aviv; Vogel, Hannes; Bergles, Dwight; Suva, Mario; Malenka, Robert; Monje, Michelle
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 2
• Page Start: ii73
• Page End: ii73
• Publication Date: 2019-04-23
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz036.042
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Pediatric high-grade gliomas (pHGGs) are a lethal group of cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors into the tumor microenvironment represents part of the mechanism by which neuronal activity influences pHGG growth, but this alone is insufficient to explain the magnitude of the effect that activity exerts on glioma progression. Here, we report that neuron-glioma interactions include bona fide synaptic communication. Single cell transcriptomic analyses of primary pediatric and adult glioma samples reveal unambiguous expression of synaptic genes by malignant glioma cells. Whole cell patch clamp recordings from xenografted, pediatric patient-derived glioma cells revealed the existence of AMPAR-mediated excitatory neurotransmission between pre-synaptic glutamatergic neurons and post-synaptic glioma cells. Millisecond timescale excitatory post-synaptic currents (EPSCs) that are depolarizing were observed in a subpopulation of pHGG cells and are associated with activity-induced glioma cell calcium transients. These excitatory axon-glioma synapses are reminiscent of the axon-glial synapses formed between neurons and oligodendrocyte precursor cells. A second electrophysiological response characterized by a prolonged (>1 sec) depolarization in response to neuronal activity was also observed. These longer duration currents are blocked by gap junction inhibitors, supporting the concept that gap junction-mediated tumor interconnections, such as observed with tumor microtubes, can function as an electrically coupled network. As neurotransmitter-mediated depolarization of normal neural precursor cells can profoundly affect precursor cell proliferation, differentiation and survival, we tested the hypothesis that depolarizing currents in pediatric glioma cells promote tumor growth. Using in vivo optogenetic techniques to depolarize xenografted pHGG cells expressing channelrhodopsin-2 (ChR2), we found that glioma depolarization robustly promoted proliferation, while expression of a dominant-negative AMPAR subunit (GluA2) that blocks neuron-glioma signaling inhibited pHGG xenograft growth and extended mouse survival. These findings suggest that integration of pediatric glioma into neural circuits promotes tumor progression.