Scientists Discover Lung Cancer Cells That Function Like Brain Neurons

Scientists found that aggressive lung cancer cells create their own electrical network, helping them spread. This unique trait may reveal new treatment opportunities.

Researchers at the Francis Crick Institute have discovered that certain aggressive lung cancer cells can form their own electrical network, similar to the body’s nervous system.

This ability may help these cancer cells become less reliant on their surrounding environment and potentially enhance their ability to spread.

Small cell lung cancer (SCLC), one of the most difficult types of cancer to treat, is often already widespread by the time it is diagnosed. It primarily develops from neuroendocrine (NE) cells, which play a role in regulating air and blood flow in the lungs.

In a study published in Nature, the Crick research team investigated electrical activity in human and mouse SCLC samples to determine whether this activity contributes to the cancer’s aggressive nature.

Using neuroscience techniques, they found that the SCLC cells had gone ‘off-grid’. They were able to generate their own electrical activity, building their own electrical network within the tumor, and becoming independent of the body’s main electrical supply, including the nerves surrounding the tumor.

Keeping cancer cells fueled

Because firing electrical signals requires a lot of energy, the researchers investigated how this energy was being generated.

Over time, the team noted important changes in gene expression as the cancer progressed, resulting in some cells losing their NE identity and becoming non-neuroendocrine (non-NE) cancer cells.

They also observed that together, these cancer cells collaborated to promote tumor development. Genes enabling the electrical communication were switched on in the NE cells, and genes relating to producing a supportive environment were switched on in the non-NE cells.

The researchers saw that the NE and non-NE cells were exhibiting a similar relationship to that of neurons and astroglia – the electrical brain cells and the neighboring housekeeping cells that support them. Like processes seen in the brain, the non-NE cells were shuttling lactate, an alternative and efficient energy source for NE cells, to help power their electrical activity. Blocking the lactate pump decreased the electrical activity of NE cells, showing that this relationship is important for the tumor to support itself.

Electrical activity leads to aggression

Despite having the same cancer-causing changes in their DNA, the researchers saw in mice that the non-NE cells did not spread and start tumors elsewhere in the body. So, to determine the impact of electrical activity in the NE cells, the team used a toxin from puffer fish called tetrodotoxin (TTX), which suppresses electrical activity. They observed that TTX did not kill NE cells in a dish, but reduced their potential to form tumors long-term, with no effect on non-NE cells.

Finally, the team looked at molecular markers of increased electrical activity in a cohort of people with SCLC, finding that these markers were elevated in the cancer cells compared to adjacent healthy cells. They also observed that as the cancer progressed, non-NE cells showed markers suggesting they were increasingly pumping out lactate. These changes in the fueling pattern of NE cells is distinct from most other cancer types that can’t build their own electrical network.

Together, these results suggest that the electrical activity of the NE cells is driving the tumor’s ability to grow and spread, a major cause of cancer death in patients.

Paola Peinado Fernandez, Postdoctoral Fellow and co-lead author on the study, said: “Our work shows that NE cells in SCLC have the ability to go ‘off-grid’, starting to generate their own electrical supply, and also being fueled by supportive non-NE cells rather than the energy sources used by most other cells.

“We’ve identified a feature which makes these types of cancers more aggressive and harder to treat. We think that this acquired autonomy of cancer cells might free them from the dependency of their environment.”

Leanne Li, Head of the Cancer-Neuroscience Laboratory at the Crick, said: “We knew that some cancer cells can mimic neural behavior, but we didn’t know how developing an independent electrical network might impact the development of disease. By combining neuroscience and cancer research techniques, we’ve been able to look at this disease from a different perspective.

“There’s still a long way to go to understand the biological impact of this electrical activity and the specific disease mechanisms that make the tumor more aggressive and harder to treat. But we hope that in understanding the way these cancer cells are fueled, we can also expose vulnerabilities that could be targeted with future treatments.”

The next steps for the research team are to study the impact of electrical activity in other types of cancers and investigate whether targeting this property in small cell lung cancer could reveal new treatment options.

Reference: “Intrinsic electrical activity drives small-cell lung cancer progression” by Paola Peinado, Marco Stazi, Claudio Ballabio, Michael-Bogdan Margineanu, Zhaoqi Li, Caterina I. Colón, Min-Shu Hsieh, Shreoshi Pal Choudhuri, Victor Stastny, Seth Hamilton, Alix Le Marois, Jodie Collingridge, Linus Conrad, Yinxing Chen, Sheng Rong Ng, Margaret Magendantz, Arjun Bhutkar, Jin-Shing Chen, Erik Sahai, Benjamin J. Drapkin, Tyler Jacks, Matthew G. Vander Heiden, Maksym V. Kopanitsa, Hugh P. C. Robinson and Leanne Li, 12 February 2025, Nature.
DOI: 10.1038/s41586-024-08575-7