Are lung cancer tumors hijacking the nervous system?

by Isabella Davis, Salk Institute

edited by Sadie Harley, reviewed by Andrew Zinin

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According to the Cleveland Clinic, a quarter of cancer deaths can be attributed to one source: cachexia. Cachexia is a syndrome that accompanies underlying chronic illness and causes unwanted muscle and fat loss, reducing quality of life and sometimes even limiting treatment options.

A new study led by Thales Papagiannakopoulos, Ph.D., an incoming Salk professor, published in Science, points to a potential new target for preventing cachexia.

The researchers found that a common genetic subset of lung cancer is more prone to cachexia and that tumors from this subtype talk to the brain through sensory neurons in the lung. Silencing these sensory nerves to disrupt the tumor-to-brain connection reduced cachexia, as did blocking the production of the lipid signaling molecule prostaglandin E2 (PGE₂) through dietary changes.

The team suspects that the tumors use PGE₂ to communicate with the nervous system, suggesting that blocking this communication could be a powerful therapeutic strategy to improve patient outcomes.

"These lung cancer tumors are essentially controlling human behavior by tapping into the nervous system and hijacking local lung sensory neurons," says senior author Papagiannakopoulos, who conducted the research at the New York University (NYU) Grossman School of Medicine.

"This role of the peripheral nervous system in cancer cachexia is entirely novel, and I think it could point us to really exciting translational opportunities that could drastically improve cancer care."

What did we already know about cachexia?

A 2015 German study reported that cachexia affects roughly half of cancer patients and also accompanies other chronic illnesses, like Alzheimer's disease or cardiovascular disease—ultimately affecting roughly 9 million people globally.

Cachexia begins with a high demand for energy—during chronic illness, the body suddenly needs much more energy to fuel the necessary immune response. From there, patients often experience appetite loss, and their muscles and fat begin to waste away as the body uses them for fuel.

These symptoms have long been assumed to be the neurological effects of circulating immune factors associated with chronic illness. But this assumption was largely due to a lack of laboratory models that would provide deeper insight into the mechanisms underlying cachexia.

Existing models for studying cachexia in cancer often have tumors growing in the wrong locations and at sizes that aren't in scale with human counterparts.

"By creating a model of cachexia that is more physiologically relevant, we can make more specific, relevant discoveries," says first author Michael Cross, a graduate student researcher in Papagiannakopoulos' lab at NYU.

"Like finding that one subtype of lung cancer tumor promotes cachexia more than others, and that those tumors actually locally communicate with the peripheral nervous system."

How does a lung tumor talk to the brain?

The researchers started by developing the most physiologically relevant mouse models of lung cancer to date—ones where tumors grow in the appropriate locations, at reasonable sizes. They looked at several different subtypes of lung cancer and found that one subtype was promoting cachexia while the others were not.

Since these mice were eating less, the researchers tried increasing the calorie and fat content of their chow to help them gain weight. To their surprise, the high-fat, high-calorie diet made things worse. Why?

Papagiannakopoulos recalled a recent finding by a collaborator showing that sensory neurons in the lungs could sense the flu, communicate that to the brain, and promote sickness and cachexia symptoms. He wondered: Could this lung-brain superhighway carry messages from cancer cells, too?

To find out, the team delved straight into the nervous system. They tested whether blocking half the sensory connections between the lungs and the brain or fully deactivating the lung-based nerves would alleviate cachexia symptoms. And they did.

"Well, then we had more questions," says Papagiannakopoulos. "What is the signal that the tumors are sending to the nerves? And why is it worse with a high-fat diet?"

The cachexia-promoting lung cancer subtype was producing much higher levels of PGE₂ than the other tumor subtypes. PGE₂ is well known for inducing symptoms of infection, including fever.

When the team modified the model mice genetically so they could no longer produce PGE₂, cachexia did not develop. Cachexia also did not develop in smaller trials in which mice were given aspirin and ibuprofen, which block the body's ability to make PGE₂.

Cachexia could also be prevented with dietary changes. PGE₂ is derived from animal fats, like omega-6 fatty acids. By switching from high-fat diets to those that contain only omega-3 fatty acids instead, the body's ability to make PGE₂ was limited, and the tumors could no longer use the signaling molecule to communicate with the nervous system and brain to cause cachexia.

Could a dietary switch change cancer outcomes?

The research unlocks an entirely new therapeutic area for treating cachexia and improving lung cancer care. Foundational studies like this can also reveal new uses for existing medications, such as aspirin and ibuprofen, and show how simple lifestyle changes can alter disease outcomes.

"Now that we know tumors are hijacking the nervous system, we want to pinpoint exactly which neurons they use to do that and what circuits in the brain they connect to," says Stefan Kotschi, MD, a postdoctoral researcher in Papagiannakopoulos' lab at NYU.

"Once we identify those neurons and circuits," explains Papagiannakopoulos, "we could see whether they are also involved in other symptoms cancer patients experience, like depression or memory loss."

By understanding the fundamental biology of how cancer-induced cachexia signals between the lungs and brain, and how dietary changes may improve patient outcomes, scientists can identify new molecules and pathways for potential therapies. Over time, these discoveries may help researchers develop more tailored treatments that can improve cancer care in the long term.

Publication details

Michael Cross et al, A dietary switch promotes sensory neuron–dependent cancer-associated cachexia, Science (2026). DOI: 10.1126/science.adz4196

Journal information: Science

Key medical concepts

CachexiaLung CancerProstaglandin E2

Clinical categories

OncologyNutrition & Healthy eatingNeurology Provided by Salk Institute Who's behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →

Andrew Zinin

Master's in physics with research experience. Long-time science news enthusiast. Plays key role in Science X's editorial success. Full profile →

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