Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1

Corina Anastasaki, Juan Mo, Ji-Kang Chen, Jit Chatterjee, Yuan Pan, Suzanne M. Scheaffer, Olivia Cobb, Michelle Monje, Lu Q. Le and David H. Gutmann ()
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Corina Anastasaki: Washington University School of Medicine
Juan Mo: University of Texas, Southwestern
Ji-Kang Chen: Washington University School of Medicine
Jit Chatterjee: Washington University School of Medicine
Yuan Pan: Stanford University
Suzanne M. Scheaffer: Washington University School of Medicine
Olivia Cobb: Washington University School of Medicine
Michelle Monje: Stanford University
Lu Q. Le: University of Texas, Southwestern
David H. Gutmann: Washington University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Neuronal activity is emerging as a driver of central and peripheral nervous system cancers. Here, we examined neuronal physiology in mouse models of the tumor predisposition syndrome Neurofibromatosis-1 (NF1), with different propensities to develop nervous system cancers. We show that central and peripheral nervous system neurons from mice with tumor-causing Nf1 gene mutations exhibit hyperexcitability and increased secretion of activity-dependent tumor-promoting paracrine factors. We discovered a neurofibroma mitogen (COL1A2) produced by peripheral neurons in an activity-regulated manner, which increases NF1-deficient Schwann cell proliferation, establishing that neurofibromas are regulated by neuronal activity. In contrast, mice with the Arg1809Cys Nf1 mutation, found in NF1 patients lacking neurofibromas or optic gliomas, do not exhibit neuronal hyperexcitability or develop these NF1-associated tumors. The hyperexcitability of tumor-prone Nf1-mutant neurons results from reduced NF1-regulated hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function, such that neuronal excitability, activity-regulated paracrine factor production, and tumor progression are attenuated by HCN channel activation. Collectively, these findings reveal that NF1 mutations act at the level of neurons to modify tumor predisposition by increasing neuronal excitability and activity-regulated paracrine factor production.

Date: 2022
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DOI: 10.1038/s41467-022-30466-6

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