Unlikely Partners: How Neurons Help Lung Cancer Tumors Grow in the Brain

In a recent study led by researchers from Stanford University and Brigham and Women’s Hospital, it was discovered that lung cancer cells in the brain partner with neurons to promote tumor growth. This discovery is a significant step toward potential treatments, as this aggressive type of cancer is difficult to treat.

Small cell lung cancer (SCLC) is a deadly disease that makes up 15% of all lung cancers, resulting in 200,000 deaths annually. This cancer is fast-growing and aggressive, often spreading to the brain, which makes treatment options limited. New research on how SCLC interacts with neurons is a crucial step toward more potential treatments. The researchers in this study discovered that SCLC cells can form connections called synapses with neurons, which speeds up tumor growth. This new information could be used to slow tumor growth in the brain if the neuron-SCLC interaction can be disrupted.

Neurons are cells that make up nerves and the brain, and they use chemical and electrical signals to communicate. Electrical signals travel through a neuron until they reach a synapse, a junction between neurons. Here, chemical signals called neurotransmitters relay the message across the short gap.

Neurons often work with cancer cells through tumor innervation, which is the interaction of nerves with a tumor. This interaction supports the tumor by promoting growth and metastasis, the process by which cancer cells spread to new locations. The Stanford and BWH researchers aimed to fill gaps in knowledge about how the nervous system interacts with small cell lung cancer specifically.

To study these interactions, the researchers used both human and mouse cells. They grew SCLC cells with or without mouse neurons and compared the cancer cell growth rates. For both human and mouse SCLC cells, one major effect was clear: the presence of neurons sped up cancer growth.

The researchers then used a toxin called tetrodotoxin to confirm that the increased SCLC growth rate was caused by neuron messaging. Tetrodotoxin, which is found in pufferfish, works by blocking electrical signals. They identified that tetrodotoxin stopped the fast SCLC growth, supporting that the electrical signals necessary for normal neuron function were related to tumor growth.

Chemical structure of tetrodotoxin (TTX), Lago et al, 2015. Creative Commons License.

Neuron activity boosts SCLC growth, but how exactly are the cells communicating with each other? The researchers discovered that SCLC cells formed direct synapses with neurons using immunogold electron microscopy. In this technique, proteins tagged with gold particles bind to a specific cellular target, which makes the target easier to see through an electron microscope. Using this method, researchers identified that SCLC cells were on the receiving side of synapses, essentially imitating normal neurons.

To imitate neurons, these SCLC cells had different active genes than SCLC cells found in other parts of the body, such as the lungs. This difference in gene expression allowed these SCLC cells in the brain to act as receivers in a synapse, as genes determine a cell’s function.

Additionally, other SCLC cells expressed traits characteristic of astrocytes, which are cells that do not directly send electrical signals and instead support neurons. This indicates that SCLC cells can take on the roles of multiple different “normal” cell types in the nervous system, forming complex networks that support tumor growth in the brain.

To test whether their findings were true in the brain, the researchers used mice with specific genetic modifications. These mice have neurons that are sensitive to blue light, allowing researchers to use small light implants in the mice’s heads to “turn on” specific neurons. The researchers’ earlier findings were consistent in this live model: when neuron activity was turned on, SCLC tumors grew faster.

With this communication between cancer cells and neurons identified, the researchers tested whether they could stop this messaging to slow tumor growth in mice. They tested levetiracetam, which is an anti-seizure medication that blocks electrical signals, and found that this treatment slowed SCLC growth in the brain.

Although synaptic connections were identified between neurons and SCLC cells, the specific signaling steps that encourage SCLC to grow aren’t well understood. If these processes are researched, potential weak points in the messaging pathway could be identified and then disrupted. These findings also encourage investigation into other cancers that metastasize to the brain, as they may grow using similar interactions to those seen with SCLC.

With each step forward in cancer research, new gaps in knowledge are uncovered. This makes innovative cancer research, such as this study, crucial to understanding the diseases that impact so many people’s lives.

By Amelia DeHoff and Celia DiNitto

References

Gysler, S. M., & Drapkin, R. (2021). Tumor Innervation: Peripheral nerves take control of the tumor microenvironment. Journal of Clinical Investigation, 131(11). https://doi.org/10.1172/jci147276

Lago, J., Rodríguez, L., Blanco, L., Vieites, J., & Cabado, A. (2015). Tetrodotoxin, an extremely potent marine neurotoxin: Distribution, toxicity, origin and therapeutical uses. Marine Drugs, 13(10), 6384–6406. https://doi.org/10.3390/md13106384

Savchuk, S., Gentry, K. M., Wang, W., Carleton, E., Biagi-Junior, C. A., Luthria, K., Yalçın, B., Ni, L., Farnsworth, H. C., Davis, R. A., Drexler, R., Melms, J. C., Liu, Y., Acosta-Alvarez, L., Hartmann, G. G., Pavarino, E. C., LaBelle, J., Woo, P. J., Toland, A. M., … Venkatesh, H. S. (2025a). Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis. Nature. https://doi.org/10.1038/s41586-025-09492-z