Researchers uncover that within the NF1 most cancers predisposition syndrome, hyperactive neurons drive tumor development
Neurofibromatosis sort 1 (NF1) sufferers develop tumors on nerves all through their our bodies. These tumors are sometimes benign, that means they don’t unfold to different components of the physique and are usually not thought-about life-threatening; nonetheless, they’ll nonetheless trigger severe medical issues, akin to blindness, once they type within the mind and nerves.
Researchers at Washington University School of Medicine in St. Louis found that neurons with a mutation within the Nf1 gene are hyperexcitable and that suppressing this hyperactivity with lamotrigine, a drug authorized by the FDA to deal with epilepsy, stops tumor development in mice.
“Tumors are very common in people with NF1,” mentioned senior creator David H. Gutmann, MD, Ph.D., the Donald O. Schnuck Family Professor and director of the Washington University Neurofibromatosis (NF) Center. “We’ve shown that we can block the growth of NF1 tumors by shutting off neuronal hyperexcitability. We’ve done it now a couple of different ways, and there’s no question that repurposing antiepileptics are an effective way to inhibit tumor growth, at least in mice. This underscores the critical role that neurons play in tumor biology.”
The research is revealed on May 19th in Nature Communications.
NF1 is a genetic disorder that affects one out of every 3,000 people on the planet. Mutations in the NF1 gene cause the condition. The disorder can affect any part of the body, but the most common symptoms are light brown spots on the skin, benign nerve tumors called neurofibromas, brain and optic nerve tumors, bone deformities, and cognitive differences such as autism, learning disabilities, and attention deficit hyperactivity disorder.
Last year, Gutmann and Michelle Monje, MD, Ph.D., a neurology professor at Stanford University School of Medicine and a Howard Hughes investigator, discovered that light increases neuronal activity in the eyes of Nf1-mutant mice, causing tumors to form on the optic nerve, which connects the eyes and the brain. In the new study, they — along with first author Corina Anastasaki, Ph.D., an assistant professor of neurology at Washington University, and co-author Lu Q. Le, MD, Ph.D., a professor of dermatology at the University of Texas, Southwestern Medical Center — investigated how increased neuronal activity leads to tumors in people with NF1.
The researchers studied neurons from mice with and without Nf1 gene mutations. At baseline, neurons from mice with tumor-causing Nf1 mutations fired electrical impulses more frequently than neurons from normal mice. These hyperexcitable neurons then released molecules that increased the growth of brain and nerve tumors. This hyperexcitability, the researchers discovered, was the result of a dysfunctional ion channel that changed the baseline electrical activity inside the neurons.
They also studied mice with an Nf1 mutation seen in people with NF1 who do not develop brain or nerve tumors. Anastasaki found that neurons from mice with this specific Nf1 mutation are not hyperexcitable and do not develop tumors – providing the first explanation for why this group of patients with NF1 lack optic gliomas or neurofibromas.
Hyperexcitable neurons are also a feature of epilepsy, and the epilepsy medication lamotrigine targets the same ion channel disrupted in hyperexcitable Nf1-mutant neurons. The researchers gave lamotrigine to a group of Nf1-mutant mice that develop optic nerve tumors. Compared to mice receiving a placebo, mice that had received the drug had smaller tumors, which no longer were growing.
Apart from suggesting a new way to treat NF1 tumors, these findings also suggest a new way of thinking about the origins of the disorder’s cognitive symptoms.
“The mutation in the Nf1 gene changes the basic biology of the neuron,” Gutmann said. “During development, neurons form first and tell the rest of the brain how to form. If you have a mutation that affects how neurons behave, that may change everything about how the brain gets set up during development. Nothing we’ve tried so far to prevent learning disabilities has worked. Maybe this discovery could lead to new treatments for the learning and cognitive problems in children with NF1.
“I’m very excited about the scientific and medical implications of these findings. Not hyperexcited,” he added, “but excited.”
Reference: “Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1” by 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, 19 May 2022, Nature Communications.