The role of neuronal activity in glioma growth and progression
- High-grade glioma (HGG) is the leading cause of brain tumor death in both children and adults. Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of HGG. 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 feed-forward 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. We next sought to determine if neuronal activity similarly promotes invasion and migration of pediatric HGG (pHGG), and to elucidate the mechanisms that mediate this effect. Diffuse infiltration is a characteristic hallmark of pHGG, but the molecular and cellular determinants of this behavior are incompletely understood. Using in vitro invasion assays, we demonstrate that exposure to activity-regulated secreted factors in conditioned medium from optogenetically stimulated and spontaneously active cortical slices increases the degree of pHGG cell infiltration through Matrigel, but that silencing neuronal activity with tetrodotoxin abrogates the pro-infiltrative effect. This effect was observed only when pHGG cells were seeded together with conditioned medium; pHGG cells do not preferentially migrate towards conditioned medium versus plain medium, suggesting that factors secreted into conditioned medium in an activity-dependent manner influence migration/invasion by inducing a pro-infiltrative phenotype rather than acting as chemoattractants. Taken together, these data indicate that active neurons play an important role in pHGG progression as well as growth. Candidate pro-infiltrative factors identified by proteomic analyses of conditioned media, including lead candidates 78-kDa glucose-regulated protein (GRP78) and cartilage acidic protein 1 (CRTAC1, or LOTUS), are presently undergoing necessity testing, and if confirmed in vivo, may represent new approaches to targeting the diffuse spread of these devastating tumors.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Johung, Tessa Blair
|Stanford University, Department of Stem Cell Biology and Regenerative Medicine.
|Oro, Anthony, 1958-
|Oro, Anthony, 1958-
|Statement of responsibility
|Tessa Blair Johung.
|Submitted to the Department of Stem Cell Biology and Regenerative Medicine.
|Thesis (Ph.D.)--Stanford University, 2016.
- © 2016 by Tessa Blair Johung
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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