Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion

By H. Venkatesh, Tessa B. Johung, V. Caretti, A. Noll, Yujie Tang, S. Nagaraja, Erin M. Gibson, Christopher W. Mount, Jai S. Polepalli, S. Mitra and 6 more. Cell, 2015

798 citations recorded by the source corpus.

SUMMARY Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.

Subfields: Cancer Research, Developmental Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fb3d46f7a5dd83a3148483790ba66485f6de3ed9

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. J. Joyce
2. Aviv Regev
3. D. Quail
4. R. Weinberg

In Developmental Neuroscience

1. Michelle Monje
2. R. Malenka
3. Fred H. Gage

In Molecular Biology

1. R. Malenka
2. Aviv Regev
3. Suzanne J. Baker
4. J. Joyce
5. D. Quail
6. Nir Yosef
7. Gina G. Turrigiano
8. Fabian J Theis

Citations in the corpus

• The microenvironmental landscape of brain tumors (2017, background): “In human glioblastoma, NLGN3 was inversely associated with survival (Venkatesh et al., 2015).”
• Neuronal activity-dependent control of postnatal neurogenesis and gliogenesis (2018, neutral): “In the nervous system, mAChRs and nAChRs are present on neurons at both synaptic and extrasynaptic sites (Huh & Fuhrer 2002, Mrzljak et al. 1993, Vizi & Lendvai 1999) as well as on glial cells (De Angelis et al. 2012, Loreti et al. 2006).”
• Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma (2017, background): “Indeed, neuronal communication with pGBM and DIPG cells is a recently demonstrated microenvironmental driver of pediatric glioma growth (Qin et al., 2017; Venkatesh et al., 2015).”
• Electrical and synaptic integration of glioma into neural circuits (2019, positive): “Appreciating the crosstalk between neurons and the glioma cells invading and integrating into neural circuitry elucidates promising therapeutic targets, including activity-regulated secreted growth factors 1,2 , neuron-to-glioma neurotransmission, ion channels and gap-junction coupling.”