Originally published in Medscape
Filippo Beleggia, MD, PhD, didn’t believe his own data. As a postdoctoral researcher, he spent years in the laboratory of Christian Reinhardt, MD, PhD, at the University Hospital Cologne, Cologne, Germany, screening genes in mice genetically engineered to develop small cell lung cancer (SCLC), hunting for the drivers of one of medicine’s deadliest malignancies.
The screen worked, flagging expected cancer genes. But it also kept returning something that seemed impossible: genes for synapses, glutamate receptors, and neural signaling pathways.
“We absolutely were not expecting it,” Beleggia recalled. “And in fact, we resisted that for a while.”
Because the team was screening for genes in lung tumors, there shouldn’t have been a reason for them to see genes needed for neural communication.
Meanwhile, thousands of miles away at Stanford Medicine in Palo Alto, California, pediatric neuro-oncologist Michelle Monje, MD, PhD, faced the same peculiar question from a different angle. Though she had spent a decade proving gliomas form functional synapses with neurons, it hadn’t occurred to her that a tumor outside the brain could be doing the same thing.
Humsa Venkatesh, PhD, postdoctoral researcher at the time and now assistant professor of neuroscience at Harvard University in Boston, proposed something unique.
“It was her [Venkatesh’s] idea,” Monje recalled. “She came into my office and said, ‘Michelle, what do you think about neuroendocrine tumors? Do you think cancers that have these neural features might be doing the same thing?’”
Two teams, two continents, one important discovery. Teams in Germany followed genes in lung tumors that kept pointing toward the brain, while the Stanford team started from the opposite direction, extending principles from brain cancer to ask whether tumors that migrate to the brain could hijack neural circuits the way gliomas do.
These parallel investigations, one led by Beleggia, Reinhardt, and colleagues, the other led by Venkatesh, Monje, and colleagues, were published simultaneously in Nature. Both tell the story of how SCLC cells form functional connections by synapsing with neurons.
Through synaptic signaling mechanisms, SCLC cells receive chemical signals that trigger electrical changes and surges of calcium in cancer cells, fueling their growth and tumor progression. In effect, SCLC cells hijack the communication pathways that neurons normally use for learning and memory.
The stakes of this discovery couldn’t be higher. SCLC accounts for 15% of all lung cancers but claims over 200,000 lives annually worldwide. Median survival is only 12 months, and 60% of patients already have brain metastases at diagnosis. Despite aggressive chemo-immune therapy, responses typically fade within months.
But now, the very drugs neurologists prescribe for epilepsy, amyotrophic lateral sclerosis (ALS), and migraines might be repurposed to disrupt SCLC’s neural communication — potentially slowing tumor growth by starving cancer cells of the electrical signals they’ve learned to exploit.
When Genetic Screens Betray Expectations
Reinhardt, the lead corresponding author with Beleggia of one of the studies and chair of the Department of Hematology and Stem Cell Transplantation at University Hospital Essen in Essen, Germany, didn’t originally set out to study cancer neuroscience.
In 2012, his team at the University Hospital Cologne designed a genetic screen experiment using transposons to identify which genes drive SCLC growth. Transposons are segments of DNA that can move around and insert throughout the genome, hence their more colloquial term “jumping genes.” By screening hundreds of tumors, the genes repeatedly disrupted by these insertions reveal themselves as cancer drivers.
The screen flagged usual suspects like the genes PTEN, NFIB, CREBBP, and TP73, which are often mutated in SCLC cases, as well as other cancers.
But it also kept flagging genes that made no sense for lung cancer: NRXN1, NLGN1, DCC, and RELN. All these genes are for building synapses in the brain.
“When we first looked at the data, I was convinced this was an artifact,” Reinhardt said. “Seeing so many neural genes was surprising to us.”
His skepticism was justified. Biological screens can produce false positives through contamination or statistical flukes. But when his team ran the same screen in lymphoma — a blood cancer — they found only typical cancer genes. Genes for synaptic formation were absent. This meant nothing was wrong with their methods. Genes for building neural connections were genuinely appearing in lung tumors.
“That was the first thing that made us think maybe it’s actually real,” Reinhardt recalled.
Reality became undeniable when Beleggia, now leading his own group, examined human data. More than 400 SCLC samples turned up mutations in synaptic genes.
But finding synaptic genes in a screen and seeing synaptic connections are two different things. Proving the latter demanded experiments that most cancer labs weren’t equipped to perform.
For months, Reinhardt’s and Beleggia’s teams wrestled with technical nightmares, struggling to stain nerve fibers in tumors that already expressed many neuronal markers. They needed a definitive functional test.
They teamed with neuroscientists Matteo Bergami and Elisa Motori from the University of Cologne, Cologne, Germany, and Max Anstötz from the Heinrich Heine University Düsseldorf, Düsseldorf, Germany. Bergami exposed cancer cells to the rabies virus as a definitive test for synaptic connection. Synapses work like one-way streets. Information flows from the presynaptic neuron to the postsynaptic neuron. The rabies virus exploits this architecture, traveling backward across synapses from infected cells to connected neurons, acting as a neurobiological tracer.
Surprisingly, the rabies virus jumped from cancer cells to nerve cells. This meant the cancer cell had successfully disguised itself as a functional part of the brain’s own wiring: a neuron. It had then formed synapses with real neurons. Otherwise, there’s no reason the rabies virus should have jumped from a cancer cell to a neuron.
“The rabies experiment was really the first proof that the synapses exist,” Beleggia said. “We thought they were there, but we had no proof…but from there on, we knew the synapses were there, and then it was about characterizing them.”
Electron microscopy made the impossible visible. In mice brain tissue samples, the imaging captured neurons forming classical synapses directly onto cancer cells, complete with all the anatomical hallmarks.
They could see a presynaptic bouton (the neuron’s signaling terminal) packed with neurotransmitter-filled vesicles pressed against the cancer cell membrane. And between them was a synaptic cleft spanning just 20 nm, the exact width of neuron-to-neuron synapses. The structures were very similar to synapses connecting brain cells to each other.
Strikingly, they also observed clear transmission of electrochemical signals mediated by glutamate between the neurons and the cancer cells — now with the help of Anstötz.
Across the world, Monje’s team saw the same structures in brain metastases. Using electron microscopy on SCLC cells implanted into mouse brains, they captured complete synapses connecting neurons directly to cancer cells, with postsynaptic densities inside tumor cells and vesicles clustered in neurons, ready to release the neurotransmitters glutamate and gamma-aminobutyric acid (GABA) onto malignant receivers.
“Boy, was I surprised to find that that hypothesis was right,” Monje recalled. “I had my head in my hands in my office, thinking, ‘How are we going to fight this for patients now if it’s actually becoming part of the neural circuit?’”
For a neuro-oncologist who’d spent years studying how brain tumors exploit neural activity, the implication was devastating. This lung cancer had learned the brain’s own trick. But unlike gliomas that arise from neural tissue, SCLC starts in the lungs and brings its neural wiring with it.
Born Wired
Reinhardt’s insight explained the paradox: “I think what happens in small cell lung cancer is that the cell of origin, the pulmonary neuroendocrine cells, are innervated. They inherit this feature because they can derive a growth advantage from innervation.”
By inheriting the ability to innervate, SCLC cells are born connected. Monje’s team tested this hypothesis in mice by cutting the vagus nerve. Two months after denervation, the initiation of tumors was either delayed or prevented entirely, and existing tumor development was also prevented.
But timing mattered. Early denervation worked, while late intervention barely helped. The cancer still evolved but was no longer dependent on local nerves because it found new sources of input in the brain itself.
“I think neuroendocrine differentiation is one of the classic features that people have known about, but it was never realized that this is a central feature of small cell lung cancer that drives its proliferation. It’s really part of the cancer phenotype,” explained Beleggia. “I think many of the problems that we have with small cell lung cancer, such as the fact that it’s not really visible to the immune system, its strong proliferation, its resistance to therapy…they’re all linked to this neuronal phenotype.”
When Thought Becomes Fuel
Monje’s team sought to answer whether the cancer was just feeding on chemicals released by active neurons or actively hijacking the electrical signal itself.
To find out, they installed light-sensitive “on switches” into specific cells, a technique called optogenetics. By shining a blue light onto the areas with these switches, they could remotely control only the cells they wanted.
First, they proved the connection by installing these light switches on neurons. When they shone light onto the neurons to activate them, cancer proliferation increased from 40% to 60%.
But the bombshell finding came next. To see if the cancer was responding to the signal itself, not just the neuron’s chemical by-products, they bypassed the neurons and put the light switches directly onto the cancer cells.
When they shined the light, the cancer cells activated, their membranes “depolarized,” and the tumors approximately doubled in size. This meant the cancer cells had learned to interpret the brain’s most basic electrical signal as a direct instruction to multiply, akin to a hidden, insidious strategy that co-opts and subverts the brain’s vital functions.
But this electrical activity is a “very metabolically expensive thing” for cancer to do, Monje said. Every time a cell fires, it must burn the cell’s main energy currency, adenosine triphosphate, to relax its activity during “repolarization.” The cancer wouldn’t be wasting all that energy unless it was getting a huge survival advantage from it.
“There’s a moment of humility as a clinician to look at the cancer cell doing something as devious as this,” Monje added.
Repurposing Brain Drugs for Peripheral Cancers
For Monje, this new understanding goes beyond an academic breakthrough. Rather, it’s a personal mission. “As a practicing neuro-oncologist, I want my patients to do better,” she said. “I want outcomes to improve.” This discovery, she feels, is the “enormous missing piece of the puzzle that, if we now address, will improve outcomes.”
That address is already being planned. The most promising path forward is to repurpose old drugs. Both teams tested FDA-approved neurologic drugs. Riluzole, approved for ALS, inhibits glutamate release. Combined with standard chemotherapy in mice, it extended median survival from approximately 60 to 81 days.
Levetiracetam, a common antiepileptic, also reduced tumor burden. The drugs worked, were well tolerated, and were inexpensive.
“I’m very excited about [repurposing brain drugs to treat SCLC],” Beleggia said. “I think this new option of using established drugs from neurology and psychiatry for small cell lung cancer, a cancer in which we have no really good therapeutic strategy, is amazing.”
Reinhardt, whose team is planning a clinical trial in Germany, agrees the potential arsenal is vast. “Many neuroactive compounds have been developed for all kinds of diseases…so they could possibly be repurposed.” He remains cautious, stressing that “we don’t have any randomized clinical data yet.”
Monje argues that clinical trials should test safe, repurposed neurologic drugs — such as levetiracetam — by adding them to standard care and testing them as “helper medicines that are going to make those strategies work better.”
She stresses this new understanding is also critical for patient safety, warning that some common symptomatic drugs could be “inadvertently harmful” by accidentally enhancing the very synaptic pathways the cancer uses to grow. “Benzodiazepines…when given to mice bearing the kind of pediatric high-grade glioma that has GABAergic synapses, actually accelerated growth and decreased survival because it augmented the synaptic biology in the cancer cells…it’s really important that we understand the neurophysiology of cancers [to know which drugs to repurpose],” Monje cautioned.
For the first time, however, the conversation between cancer and the brain is one that, with the right tools, modern medicine may finally learn to disrupt.
Monje reported holding equity in MapLight Therapeutics and Stellaromics and stock in CARGO Therapeutics. She was previously on the scientific advisory board for Cygnal Therapeutics. Reinhardt received consulting and lecture fees from AbbVie, AstraZeneca, Vertex, and Merck. He also received research funding from AstraZeneca and Gilead Pharmaceuticals and is a co-founder of CDL Therapeutics.