NF1 mutation-driven neuronal hyperexcitability sets a threshold for tumorigenesis and therapeutic targeting of murine optic glioma

Authors

• Corina Anastasaki, Washington University School of Medicine, St. Louis, MO
• Jit Chatterjee, Washington University School of Medicine, St. Louis, MO
• Joshua P. Koleske, Washington University School of Medicine, St. Louis, MO
• Yunqing Gao, Washington University School of Medicine, St. Louis, MO
• Stephanie L. Bozeman, Washington University School of Medicine, St. Louis, MO
• Chloe M. Kernan, Washington University School of Medicine, St. Louis, MO
• Lara I Marco Y Marquez, Washington University School of Medicine, St. Louis, MO
• Ji-Kang Chen, Washington University School of Medicine, St. Louis, MO
• Caitlin E. Kelly, Washington University School of Medicine, St. Louis, MO
• Connor J. Blair, Washington University School of Medicine, St. Louis, MO
• Dennis J. Dietzen, Washington University School of Medicine, St. Louis, MO
• Robert A. Kesterson, Pennington Biomedical Research Center, Baton Rouge, LA
• David H. Gutmann, Washington University School of Medicine, St. Louis, MO

Document Type

Article

Publication Date

4-12-2024

Publication Title

Neuro-Oncology

Abstract

Background: With the recognition that noncancerous cells function as critical regulators of brain tumor growth, we recently demonstrated that neurons drive low-grade glioma initiation and progression. Using mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG), we showed that Nf1 mutation induces neuronal hyperexcitability and midkine expression, which activates an immune axis to support tumor growth, such that high-dose lamotrigine treatment reduces Nf1-OPG proliferation. Herein, we execute a series of complementary experiments to address several key knowledge gaps relevant to future clinical translation. Methods: We leverage a collection of Nf1-mutant mice that spontaneously develop OPGs to alter both germline and retinal neuron-specific midkine expression. Nf1-mutant mice harboring several different NF1 patient-derived germline mutations were employed to evaluate neuronal excitability and midkine expression. Two distinct Nf1-OPG preclinical mouse models were used to assess lamotrigine effects on tumor progression and growth in vivo. Results: We establish that neuronal midkine is both necessary and sufficient for Nf1-OPG growth, demonstrating an obligate relationship between germline Nf1 mutation, neuronal excitability, midkine production, and Nf1-OPG proliferation. We show anti-epileptic drug (lamotrigine) specificity in suppressing neuronal midkine production. Relevant to clinical translation, lamotrigine prevents Nf1-OPG progression and suppresses the growth of existing tumors for months following drug cessation. Importantly, lamotrigine abrogates tumor growth in two Nf1-OPG strains using pediatric epilepsy clinical dosing. Conclusions: Together, these findings establish midkine and neuronal hyperexcitability as targetable drivers of Nf1-OPG growth and support the use of lamotrigine as a potential chemoprevention or chemotherapy agent for children with NF1-OPG.

First Page

1496

Last Page

1508

DOI

10.1093/neuonc/noae054

Rights

© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

Recommended Citation

Anastasaki, Corina; Chatterjee, Jit; Koleske, Joshua P.; Gao, Yunqing; Bozeman, Stephanie L.; Kernan, Chloe M.; Marquez, Lara I Marco Y; Chen, Ji-Kang; Kelly, Caitlin E.; Blair, Connor J.; Dietzen, Dennis J.; Kesterson, Robert A.; and Gutmann, David H., "NF1 mutation-driven neuronal hyperexcitability sets a threshold for tumorigenesis and therapeutic targeting of murine optic glioma" (2024). LSU-LCMC Cancer Center Faculty Publications. 119.
https://digitalscholar.lsuhsc.edu/llcc_facpubs/119
10.1093/neuonc/noae054