Lung Tumors Hijack Sensory Neurons via PGE2 to Drive Cancer Cachexia, Study Reveals
核心洞察
A new study in *Science* shows that LKB1 (搜索)-mutant lung tumors communicate with the brain through lung sensory neurons to drive cancer-associated cachexia (搜索).
The lipid signaling molecule prostaglandin E2 (PGE2) was identified as the key mediator; blocking PGE2 genetically or with aspirin/ibuprofen prevented cachexia (搜索) in mice.
A high-fat, high-calorie diet worsened cachexia (搜索) by increasing PGE2 production, while switching to omega-3 fatty acids limited PGE2 synthesis and prevented the syndrome.
A quarter of all cancer deaths can be attributed to cachexia (搜索), a debilitating wasting syndrome that causes severe involuntary weight loss, muscle wasting, and reduced appetite. Now, a study published in Science on July 2, 2026, reveals an entirely new mechanism behind this condition: lung tumors hijacking the peripheral nervous system to communicate directly with the brain.
Led by Thales Papagiannakopoulos, PhD, an incoming Salk professor who conducted the research at the New York University (NYU) Grossman School of Medicine, the study demonstrates that a common genetic subset of lung cancer (搜索) is more prone to cachexia (搜索) and that tumors from this subtype use sensory neurons in the lung to send signals to the brain.
"These lung cancer (搜索) tumors are essentially controlling human behavior by tapping into the nervous system and hijacking local lung sensory neurons," said Papagiannakopoulos. "This role of the peripheral nervous system in cancer cachexia (搜索) is entirely novel, and I think it could point us to really exciting translational opportunities that could drastically improve cancer care."
A Physiologically Relevant Model Reveals Subtype-Specific Cachexia (搜索)
Cachexia (搜索) affects roughly half of cancer patients and also accompanies other chronic illnesses such as Alzheimer's disease and cardiovascular disease, ultimately impacting approximately 9 million people globally, according to a 2015 German study cited by the researchers. Despite its prevalence, the mechanisms underlying cachexia have remained poorly understood, partly due to a lack of laboratory models that accurately mirror human disease.
The research team addressed this gap by developing what they describe as the most physiologically relevant mouse models of lung cancer (搜索) to date—models in which tumors grow in the appropriate locations and at clinically relevant sizes. When they examined several different subtypes of lung cancer, they found that one subtype consistently promoted cachexia (搜索) while others did not.
"By creating a model of cachexia (搜索) that is more physiologically relevant, we can make more specific, relevant discoveries," said first author Michael Cross, a graduate student researcher in Papagiannakopoulos' lab at NYU. "Like finding that one subtype of lung cancer (搜索) tumors promotes cachexia more than others, and that those tumors actually locally communicate with the peripheral nervous system."
The Paradox of High-Fat Diets
Since the affected mice were eating less, the researchers attempted a seemingly logical intervention: increasing the calorie and fat content of their chow to help them gain weight. The result was counterintuitive and alarming—the high-fat, high-calorie diet made cachexia (搜索) substantially worse, sharply reducing food and water intake as well as physical activity, and accelerating mortality even without increasing tumor burden.
This paradox prompted the team to investigate a deeper mechanism. Papagiannakopoulos recalled a recent finding by a collaborator showing that sensory neurons in the lungs could sense influenza virus, communicate that information to the brain, and promote sickness and cachexia (搜索) symptoms. He hypothesized that cancer cells might exploit the same lung-brain superhighway.
PGE2: The Molecular Messenger
The cachexia (搜索)-promoting lung cancer (搜索) subtype—characterized by mutations in the tumor-suppressing gene serine/threonine kinase 11 (LKB1 (搜索))—was found to produce significantly higher levels of prostaglandin E2 (PGE2) compared to other tumor subtypes. PGE2 is a lipid signaling molecule well known for inducing symptoms of infection, including fever, and is derived from animal fats such as omega-6 fatty acids.
When the team genetically modified mice so they could no longer produce PGE2, cachexia (搜索) did not develop. Similarly, in smaller trials, mice given aspirin and ibuprofen—drugs that block the body's ability to synthesize PGE2—were protected from the syndrome.
Dietary intervention proved equally effective. By switching from high-fat diets to those containing only omega-3 fatty acids instead of omega-6, the body's ability to make PGE2 was limited, and tumors could no longer use the signaling molecule to communicate with the nervous system and brain to cause cachexia (搜索).
Silencing the Tumor-to-Brain Connection
To confirm the neural pathway, the researchers tested whether blocking sensory connections between the lungs and the brain could alleviate cachexia (搜索). Both partial blockade of sensory connections and full deactivation of lung-based nerves successfully reduced cachexia symptoms, confirming that local tumor signals transmitted through sensory nerves to the brain contribute to the condition.
In a related Perspective published alongside the study, Yetiş Gültekin and Matthew Vander Heiden wrote: "Cachexia (搜索) probably reflects a spectrum of mechanistically distinct but phenotypically convergent states rather than emerging from a single cause. Nevertheless, defining how tumors recruit neural circuits to sustain their own metabolism and to reshape host physiology will be important to understand both cancer and cachexia biology."
Future Directions
The research opens an entirely new therapeutic area for treating cachexia (搜索) and improving lung cancer (搜索) care. It also reveals potential new uses for existing medications such as aspirin and ibuprofen, and demonstrates how dietary changes may 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," said Stefan Kotschi, MD, a postdoctoral researcher in Papagiannakopoulos' lab at NYU.
Papagiannakopoulos added: "Once we identify those neurons and circuits, 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 (搜索) signals between the lungs and brain, scientists can identify new molecules and pathways for potential therapies that may ultimately improve cancer care in the long term.