Researchers from the Francis Crick Institute have found that aggressive lung cancer cells can develop their own electric network, like that seen in the nervous system. 

This unique property could make them less dependent on the environment surrounding the tumour and even spread more easily, say the scientists. 

Small cell lung cancer (SCLC) is one of the hardest types of cancer to treat and has often already spread by the time people are diagnosed. It mainly arises from neuroendocrine (NE) cells, which help regulate air and blood flow in the lungs. 

In research published in Nature, the team at the Crick looked for electrical activity in human and mouse SCLC samples. 

They found that the SCLC cells were able to generate their own electrical activity, building their own electrical network within the tumour, and becoming independent of the body’s main electrical supply, including the nerves surrounding the tumour. 

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 fuelled 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.” 

Changes in gene expression

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 tumour 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. 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 tumour to support itself. 

Cells mimic neural behaviour

The researchers saw in mice that the non-NE cells did not spread and start tumours 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.  

TTX did not kill NE cells in a dish, but reduced their potential to form tumours 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 fuelling pattern of NE cells are distinct from most other cancer types that can’t build their own electrical network. 

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

Leanne Li, Head of the Cancer-Neuroscience Laboratory at the Crick, said: “We knew that some cancer cells can mimic neural behaviour, but we didn’t know how developing an independent electrical network might impact the development of disease. 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 tumour more aggressive and harder to treat. But we hope that in understanding the way these cancer cells are fuelled, we can also expose vulnerabilities that could be targeted with future treatments.” 

The team will now study the impact of electrical activity in other types of cancers and whether targeting this property in small cell lung cancer could reveal new treatment options. 

Diana Spencer, Senior Digital Content Editor, DDW