High-grade gliomas are the leading cause of brain tumor-related death in both children and adults. We have recently shown that cortical neuronal activity promotes the growth of high-grade glioma in vitro and in vivo. A major mechanism mediating the growth-promoting effect of neuronal activity on high grade glioma is activity-regulated secretion of the synaptic protein neuroligin-3 (NLGN3) ectodomain, which we have shown to be both sufficient and necessary in situ and in vitro. Soluble neuroligin-3 stimulates the PI3K-mTOR pathway in glioma cells and also induces feed-forward expression of glioma NLGN3, but the upstream signaling events are not yet elucidated.
In Aim 1 of this proposal, we now seek to confirm the necessity of NLGN3 for in vivo glioma growth and to determine the cellular origin(s) of secreted NLGN3 using constitutive and inducible NLGN3 genetic deletion strategies together with in vivo optogenetic techniques and patient-derived orthotopic xenograft models.
In Aim 2 we will identify the activity-regulated enzyme responsible for NLGN3 secretion using pharmacological and genetic strategies.
In Aim 3 we will identify the NLGN3 binding partner in glioma cells using the range of adult and pediatric patient-derived high grade glioma models we have developed, co-immunoprecipitation and mass spectrometric analysis. The proposed experiments will deepen our understanding of the mechanisms by which neurons promote cancer growth in the glioma microenvironment and will identify potential targets of therapy for these deadly cancers.
High-grade gliomas are the leading cause of brain tumor-related death in both children and adults. We have recently shown that the activity of neurons in the tumor microenvironment promotes the growth of high-grade glioma through secretion of a synaptic protein that functions as an unexpected growth factor for glioma. The proposed experiments seek to deepen our understanding of how this protein is secreted and to which receptor on glioma cells it binds. This will deepen our understanding of the mechanisms by which neurons promote cancer growth in the glioma microenvironment and may identify potential targets of therapy for these deadly cancers.
| Gibson, Erin M; Nagaraja, Surya; Ocampo, Alfonso et al. (2018) Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment. Cell : |
| Lin, Grant L; Nagaraja, Surya; Filbin, Mariella G et al. (2018) Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma. Acta Neuropathol Commun 6:51 |
| Gibson, Erin M; Geraghty, Anna C; Monje, Michelle (2018) Bad wrap: Myelin and myelin plasticity in health and disease. Dev Neurobiol 78:123-135 |
| Mount, Christopher W; Majzner, Robbie G; Sundaresh, Shree et al. (2018) Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Nat Med 24:572-579 |
| Venkatesh, Humsa; Monje, Michelle (2017) Neuronal Activity in Ontogeny and Oncology. Trends Cancer 3:89-112 |
| Nagaraja, Surya; Vitanza, Nicholas A; Woo, Pamelyn J et al. (2017) Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma. Cancer Cell 31:635-652.e6 |
| Mount, Christopher W; Monje, Michelle (2017) Wrapped to Adapt: Experience-Dependent Myelination. Neuron 95:743-756 |
| Venkatesh, Humsa S; Tam, Lydia T; Woo, Pamelyn J et al. (2017) Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature 549:533-537 |
| Qin, Elizabeth Y; Cooper, Dominique D; Abbott, Keene L et al. (2017) Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma. Cell 170:845-859.e19 |
| Lin, Grant L; Monje, Michelle (2017) A Protocol for Rapid Post-mortem Cell Culture of Diffuse Intrinsic Pontine Glioma (DIPG). J Vis Exp : |
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