Small cell lung cancer cells that metastasize to the brain cozy up to neurons and form working electrical connections, called synapses, according to an upcoming study led by Stanford Medicine researchers. The pulse of electrical signals to the cancer cells strongly promotes tumor growth, the researchers found.
Although interactions between neurons and cancer cells have been shown to occur in primary brain cancers (cancers that originate in the brain rather than traveling there from elsewhere in the body), the study is the first to show a similar interaction with lung cancer cells.
The discovery highlights the importance of neural signaling in cancer growth and the crafty way cancer cells co-opt cellular processes to their advantage. It also suggests the possibility of novel cancer therapies that interrupt this neuron-to-cancer cell signaling, or the repurposing of existing psychiatric or neurological medications that affect neural activity.
"We have seen metastatic cancer cells near neurons in the brain," said Michelle Monje , MD, PhD, professor of neurology. "But here, we show that in small cell lung cancer there are direct, bona fide, electrophysiologically functional synapses forming between neurons and the cancer cells, and these interactions are central to the cancer cells' growth. It's becoming ever more clear that the nervous system plays an important role in many types of cancers."
Monje, who is the Milan Gambhir Professor in Pediatric Neuro-Oncology, shares senior authorship of the study , which was published Sept. 10 in Nature, with former postdoctoral scholar Humsa Venkatesh, PhD. Venkatesh is now an assistant professor of neurology at Harvard Medical School. Stanford School of Medicine student Solomiia Savchuk and Kaylee Gentry, MS, of Harvard Medical School, are co-lead authors of the study.
A new approach to cancer research
"Understanding the emerging influence of neuronal activity has transformed how we think about brain-derived cancers, and we're now thrilled to expand this insight to a completely new group of malignancies," Venkatesh said. "For the first time, we find that metastatic cancers integrate with neuronal circuitry. This discovery has clear clinical relevance and opens promising new avenues for treatment."
The researchers collaborated with small cell lung cancer expert Julien Sage , PhD, professor of pediatrics and of genetics and the Elaine and John Chambers Endowed Professor in Pediatric Cancer. His laboratory published results in 2023 showing that small cell lung cancer cells in the brain not only begin to emulate surrounding neurons — growing long, thin protrusions called axons and becoming less rounded — but they also recruit other brain cells called astrocytes to secrete protective factors normally used to promote the survival of developing neurons.
Monje and Venkatesh's work now shows that the cells do more than just masquerade as neurons — they form functional connections that help them grow.
"Small cell lung cancer remains one of the most fatal forms of human cancer," Sage said. "I am excited about this work because it provides some new therapeutic directions to inhibit the growth of brain metastases, including molecules that have been used safely in patients with neurological disorders."
Small cell lung cancer accounts for 15% of all lung cancers and causes more than 200,000 deaths worldwide each year. More than half of these cancers have already metastasized at the time of diagnosis, and most often these metastases are to the brain. They arise from a neuroendocrine cell that releases hormones in response to signals from the nervous system. As such, the cells have similarities to both neurons and endocrine cells and are a critical part of the communication between tissue types throughout the body.
Monje and researchers in her laboratory have spent the past 15 years studying primary brain cancers called gliomas, which include a rare, rapidly fatal pediatric brain tumor known as diffuse intrinsic pontine glioma. Their discoveries of the critical role of neural signaling in brain cancer growth launched the field of cancer neuroscience.
"We've discovered that the nervous system is crucial in driving the growth and progression of primary brain cancers," Monje said. "Humsa wondered how nerves in the lung might influence the pathophysiology of small cell lung cancer, which has some neural features, and how the interactions with neurons in the brain might enable and promote growth of the brain metastases."
Affect on tumor growth
Venkatesh and Savchuk turned to a model of small cell lung cancer in laboratory mice developed in Sage's laboratory. They found that interrupting the signaling from one of two vagus nerves that run from the brain to the lungs prior to inducing the development of lung cancer had a marked effect on cancer development and growth. In some cases, no primary tumors formed at all, and no animals experienced metastasis to the liver. In contrast, control animals developed multiple lung tumors and liver metastases.
"We saw a profound effect on the tumor burden in the animals," Venkatesh said, "from the initiation of the tumor and its spread."
Blocking the function of the vagus nerve after tumors had formed slowed the growth of early-stage tumors but had little effect on more advanced cancers — suggesting that the impact of nerve signaling is most important during disease initiation and development and less important for tumor maintenance.
The researchers, including postdoctoral scholar Fangfei Qu, PhD, then investigated the growth of mouse and human small cell lung cancers implanted into the brains of laboratory mice. They found that tumors arising from cancer cells implanted near neurons became infiltrated with neurons and were dividing more quickly than tumors with less neuronal involvement. Studies of brain biopsies from nine patients with metastatic small cell lung cancer showed similar results: Neuronal axons were intermingled with cancer cells, and those cells were replicating more quickly than those in axon-free regions of the tumor.
The researchers then used a technique called optogenetics to stimulate neurons in the cortex of living animals. Optogenetics was developed by Karl Deisseroth , MD, PhD, the D.H. Chen Professor, professor of bioengineering and of psychiatry and behavioral sciences, and a Howard Hughes Medical Institute investigator.
"When we stimulated these neurons, the lung cancer placed in the cortex grew much larger and invaded more," Venkatesh said. "Further investigation showed part of this growth is mediated by growth factors secreted by the neurons in response to stimulation, but a large part of it is mediated by these functional synapses between cancer cells and neurons."
Growing the cells together in a laboratory dish showed that a drug that blocks the ability of the neurons to send electrical signals slowed the rate of growth of the cancer cells. Furthermore, genes expressed by cancer cells growing in tandem with neurons encoded proteins involved in synapse development, which was confirmed in tumor biopsies from the brains of small cell lung cancer patients.
Finally, electron microscopy clearly showed that the cancer cells structurally participate in synapses with neurons, and electrophysiological studies confirmed that a subpopulation of cancer cells generate an electrical current across their membranes in response to signaling by their partner neurons. An anti-seizure drug that interferes with signaling across synapses significantly reduced cancer cell growth and tumor burden in mice with small cell lung cancers as compared with control animals.
"It's humbling, as a clinician, to think about all of the ways that the cancer is taking advantage of the patient, and how much of this pathophysiology we have yet to understand," Monje said. "The electrical communication that drives this membrane depolarization is triggering some form of voltage sensitive signaling and promoting growth in a way that as oncologists, we haven't been thinking about enough. But now we know an important direction we need to pursue to achieve effective therapies for these currently intractable cancers."
Researchers from Brigham and Women's Hospital, Harvard Medical School, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Columbia University Irving Medical Center, and the Dana-Farber Cancer Institute contributed to the work.
The study was funded by the National Institutes of Health (grants R00CA252001, DP2CA290968, R01NS092597, DP1NS111132; P50CA165962, R01CA258384, U19CA264504, CA231997, R37NS046579, R37CA258829, R01CA266446, R01CA280414, U54CA274506 and P30CA013696), the Glaucoma Research Foundation, the Charles Hood Foundation, the Sontag Foundation, the McKnight Foundation, the Kinship Foundation, the Damon Runyon Foundation, the V Foundation, the Pew Foundation, ChadTough Defeat DIPG, the Virginia and D.K. Ludwig Fund for Cancer Research, Cancer Research UK, the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation, the McKenna Claire Foundation, the Gatsby Charitable Foundation, a Damon Runyon Cancer Research Foundation fellowship, the Stanford Medical Scholars Research Program, and the Pershing Square Sohn Cancer Research Alliance Prize. This work was additionally supported by the Herbert Irving Comprehensive Cancer Center and Columbia University's Molecular Pathology Shared Resource and Human Immune Monitoring Core.
