“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.
Read more about cancer infiltrating the nervous system.