Paola Vermeer remembers the moment in June 2019 clearly: She was standing with a cluster of colleagues around a fresh slice of a tumor removed just minutes before from a mouse model of head-and-neck cancer. It was now resting atop a microelectrode array, a device for recording electrical signals generated by living tissues. The device, though widely used in neuroscience, was an unfamiliar one for Vermeer, a cancer biologist at Sanford Research in Sioux Falls, South Dakota. But she needed it to test a hunch.
Several years earlier, Vermeer had become interested in the nerves that are often seen within cancerous tumors. Mounting evidence suggested that neuronal activity could promote tumor growth, but exactly how was still in question. “Very naively, I thought, ‘Well, nerves are electrically connecting cells,’” she says. “And so if they’re functional, there should be an electrical readout.”
Now, after a few training sessions from a Sanford colleague who uses microelectrode arrays to study mouse brains — a more typical application of the technique — and a handful of trial-and-error drills on her own, Vermeer had arrived at the moment of truth. The team gathered around the hulking microelectrode rig: a glass slide embedded with dozens of tiny electrodes and placed on the stage of a powerful microscope, surrounded by a wire cage to block other sources of electromagnetic radiation from ruining the experiment. Vermeer felt doubts creeping in.
“We put our first slice on the array, and in my head, I was like ‘Yeah, this isn’t going to work. There’s no way this is gonna work,’” Vermeer says.
The team gazed at a nearby computer screen showing a calendar-like grid of 60 boxes, representing each of the electrodes in the array. Fuzzy blue lines bisected the boxes horizontally, indicating the tissue’s weak baseline electrical activity. Then Vermeer pressed a button on the computer to stimulate an electrode on the edge of the array. Soon, wild spikes of cobalt blue began to propagate through the boxes on the screen, exposing strong electrical signals transiting through the tumor slice.
“When we saw activity, literally, my jaw dropped,” Vermeer says. “No way,” she thought. Here was evidence that nerves within malignant tissue are fully functional, akin to nerves in healthy tissues throughout the body.
Her next thought: “We need more tumors; we need to get more samples,” she says. For help with that, she turned to her collaborator and brother, Ronny Drapkin, a pathologist at the University of Pennsylvania in Philadelphia focused on gynecologic cancers, and director of an ovarian cancer biobank. Over the following months, he sent multiple shipments of live tumor tissue, bathed in transplant medium, overnight to South Dakota.
With more samples, the team demonstrated that nerves form functional circuits in both head-and-neck and ovarian tumors, and that tumors are more electrically active than normal tissues. Those results, described in a paper in Science Advances this past May, provide some of the strongest evidence yet that electrical signals drive tumor growth outside the central nervous system. The work also serves as an important extension of two independent reports in 2019 describing functional synapses within brain cancers called gliomas.
Together these findings bolster the emerging field of cancer neuroscience. Though barely more than two decades old, cancer neuroscience is already a sprawling field, dealing broadly with the cross-talk between malignant tumors and neurons in both the central and peripheral nervous systems. It encompasses topics ranging from sleep disruptions in people with cancer to the cognitive effects of chemotherapy.
“Most of the evidence, and really the center of the field, is around the idea that neurons and nerves” — via a variety of mechanisms that researchers are still teasing apart — “seem to regulate almost everything about cancer, from tumor initiation in many cases to tumor growth, tumor invasion and metastasis, probably resistance to therapy, and evolution of the disease,” says Michelle Monje, a neuroscientist and neuro-oncologist at Stanford University in California, who headed one of the teams that found synapses in gliomas.
The field sits at the intersection of two broad themes in contemporary biomedical science: the rising awareness that the nervous system guides the development of organs and tissues throughout the body, and the understanding that tumors are not just undifferentiated lumps of cells, but neo-organs in their own right.
In their interactions with neurons that drive tumor growth and progression, cancer cells are “not inventing anything new. They’re just using these mechanisms of development and plasticity” that are fundamental to normal body processes, Monje says. By studying the interactions between the nervous system and cancer, Monje, Vermeer and a growing cadre of researchers aim to learn how to treat cancer more successfully, as well as gain basic insights into the normal development and function of the nervous system.
Pathologists first spotted nerve cells lurking in tumors in the early 1900s. But their observations did not capture the attention of cancer biologists for another 100 years or so, Drapkin says. The cancer biologists tended to regard the cells as clinical curiosities, mere bystanders rather than active participants in malignancy.
Then, in 1998, a professional setback for one pathologist turned into a lucky break for the field. Gustavo Ayala had just moved from the recently defunct Allegheny University of the Health Sciences in Philadelphia, Pennsylvania to Baylor College of Medicine in Houston, Texas, and he needed a project to keep him busy while he waited for his state medical license to come through. He decided to look into perineural invasion, or the tendency for cancer cells to cluster around local nerve fibers.
“Of course, I knew about perineural invasion as a pathologist. It’s very common,” says Ayala, who is now at the University of Texas at Houston. He also knew that tumors that exhibit perineural invasion tend to be more deadly; the cancer cells use the nerves as highways to exit a primary tumor site and metastasize. “What stood out was that it was clinically very important. But nobody knew why. And nobody knew how,” he says. “So I decided to make that my research.”
Ayala developed a way to grow prostate cancer cells in laboratory dishes together with mouse dorsal root ganglia — clusters of neurons that sit just outside the spinal cord and connect the peripheral and central nervous systems. “It was pretty amazing. I mean, things happened immediately,” Ayala says, describing the method. Within 24 hours of landing in the dish, the neurons sent out long, thin filaments called neurites in the direction of the cancer cells.