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

Anastasaki C, Mo J, Chen JK, Chatterjee J, Pan Y, Scheaffer SM, Cobb O, Monje M, Le LQ, and Gutmann DH.

Neurofibromatosis-1 (NF1) is a genetic cancer predisposition syndrome associated with the development of tumors in the central and peripheral nervous systems, as well as other malignancies and abnormalities. Previous research has established that neurons and neuronal activity play a key role in the growth of NF1-related tumors including optic pathway gliomas and plexiform neurofibromas through the secretion of paracrine factors from microglia and T cells, but this relationship is not fully understood. In this study, scientists examine the role of neuronal activity in NF1-related nervous system tumor progression using a combination of human-induced pluripotent stem cell (hiPSC) and Nf1-mutant mouse lines with and without the propensity to develop nervous system cancers. To explore neuronal activity in vitro, the scientists used Axion’s noninvasive, label-free Maestro multielectrode array (MEA) platform and other methods.

Overall, the team revealed a number of findings demonstrating that NF-1 tumor-promoting mutations lead to HCN-dependent neuronal hyperexcitability in both the central and peripheral nervous system; activity-dependent paracrine secretions then drive tumor progression. In contrast, the researchers found that mice with a common NF1 mutation that is not associated with optic pathway gliomas or plexiform neurofibromas do not exhibit neuronal hyperexcitability. Importantly, the authors also identified HCN as key target and discovered that suppressing neuronal hyperexcitability with the antiseizure drug lamotrigine stops tumor growth in mice with the NF1 mutation—a promising finding that may lead to new therapeutic avenues in the field of neuro-oncology.