Cachexia is a condition in which patients with cancer or other chronic diseases become unwell and lose weight. This condition is often accompanied by symptoms of brain-related diseases, such as loss of appetite, and can lead to loss of muscle and often fat. This debilitating state can make patients unable to tolerate treatment or participate in clinical trials, so many patients end up dying from cachexia rather than cancer, the researchers said.
Despite its toll, cachexia is poorly understood and efforts to treat it have had little success. Now, a new study led by researchers at NYU Langone Health and its Perlmutter Cancer Center has uncovered a new cachexia-inducing pathway associated with lung cancer. Further successful experiments could lead to improved treatments.
Our study shows that tumors can cause cachexia by essentially hacking the nervous system and changing feeding behavior. Many groups have studied how molecules circulating throughout the body during chronic disease cause systemic effects on organs such as the brain and muscles. However, our research shows that short-range communication between tumors and nearby cells called neurons (which are connected to the brain) can cause disease and cachexia. ”
Dr. Thales Y. Papagiannakopoulos, Senior Research Scientist, Associate Professor, Department of Pathology, New York University Grossman School of Medicine, Member, Perlmutter Cancer Center
Published in a magazine science The study, published online July 2, established three different genetic mouse models of lung cancer. Each of the three groups was engineered to have changes in the DNA code (variants) that resemble patterns seen in major subtypes of human lung cancer. However, only a mutant lacking a gene called LKB1 caused cachexia in the mice. Because this mutant did not cause larger or more numerous tumors than other mutants, the researchers wondered if LKB1-deficient tumors were producing something that other mutants did not.
Mice with LKB1-deficient tumors lost both fat and muscle mass due to decreased appetite, so the researchers switched all three groups of mice to high-calorie, high-fat diets to slow weight loss. Mice with a subtype of lung cancer that did not cause cachexia quickly started gaining weight when fed a high-fat diet. However, the researchers were surprised to see that people on a high-fat diet, in which LKB1 in their tumors was inactive, ate even less, lost more weight, and began to die sooner than those on the original diet.
To understand how a high-fat diet exacerbates cachexia, the researchers collected fluid from the tumor-filled lungs of mice with LKB1-deficient tumors and measured levels of signaling molecules thought to be driving cachexia. Compared to LKB1-deficient cancer mice fed a normal diet, mice fed a high-fat diet had much higher levels of prostaglandin E2, a signaling molecule known to amplify inflammation, the influx of immune cells to the site of injury. Over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, combat pain and swelling by blocking the action of the enzyme that produces prostaglandin E2.
Even on a normal diet, mice without active LKB1 in their tumors had significantly higher levels of prostaglandin E2 than mice with other tumor mutations, indicating that prostaglandin E2 is the causative agent of cachexia produced by LKB1-deficient tumors. When the researchers inhibited the production of prostaglandin E2 genetically, with NSAIDs, or with a fish oil diet rich in anti-inflammatory omega-3 fatty acids, the mice had better survival rates and less weight loss, even when fed a high-fat diet.
Because prostaglandin E2 was elevated only in the lung fluid and not in the bloodstream, the researchers hypothesized that prostaglandin E2 likely exerts cachexia-causing effects locally in the lungs. Recent studies have shown that in pulmonary infections, illness and anorexia may be mediated by local prostaglandin E2 signals to pulmonary neurons, which then transmit signals from the lungs to the brain via the vagus nerve. The researchers blocked the vagus nerve’s ability to send signals to the brain by either surgically cutting it or genetically suppressing it. They observed that blocking vagus nerve signaling increased appetite in animals with cancer and prevented common symptoms of cachexia. This confirms that, similar to pulmonary infections, prostaglandin E2 signaling may be transmitted through pulmonary neurons that are part of the vagus nerve and act on the brain to influence feeding behavior.
Although their study was primarily conducted in mouse models, the researchers also examined lung fluid from human lung cancer patients. They found that prostaglandin E2 was significantly higher in cachectic patients, suggesting that prostaglandin E2 may play a similar role in humans and that inhibiting prostaglandin E2 production or signaling may improve outcomes in cachectic patients.
“Blocking prostaglandin E2 did not shrink the tumors, but it made the mice stronger and able to withstand the toll that lung cancer takes on their bodies,” Dr. Papagiannakopoulos said. “We hope that our research will uncover treatments for cachexia and dietary interventions by blocking harmful signals to the vagus nerve, helping patients become as strong as possible in their fight against cancer.”
This research forms part of the work of Team CANCAN, an international team funded through the Cancer Grand Challenge, a global initiative co-founded by Cancer Research UK and the National Cancer Institute. Team CANCAN brings together researchers across disciplines to elucidate the biological mechanisms that drive cancer cachexia and identify new opportunities to improve outcomes for people living with cancer.
Dr. Papagiannakopoulos said he hopes to continue investigating the role of neural signaling in cachexia and other aspects of cancer with Cancer Grand Challenge collaborators.
Funding for this research was supported by National Institutes of Health grants P30CA016087, U19NS1076, R37CA222504, R01CA227649, R01CA283049, R01CA262562, F30CA284910, MH019524, DA060339; 1R37CA286477, HD088411, NS138066, NS107616, DA063565, S10RR027926, and S10OD032292. Additional funding was provided by German Research Foundation grant KO 7112/1-1 and the Cancer Grand Challenges partnership funded by Cancer Research UK (CGCSDF 2021/100003) and the National Cancer Institute (OT2CA278609).
Other NYU Langone researchers involved in the study include co-lead authors Michael Cross and Stephen Koch, as well as Warren Wu, Phaedra Luciano-Mateo, Ezequiel Dantas, Taha Niazi, Shijia Chen, Ali Rashid-Farooqi, Ray Pillai, Jack Sanford, Jeshua Kim, Begona Gamaro-Rana, Adam C. Ma, Yuan Hao, Sahis Rajalingam, Annie Xiang, Issa, Jack A. Huang, Javon A. Kwok-King Wong, Leopold N. Segal, Marcus D. Gonsalves, and Robert C. Froemke.
Other study collaborators include Ying Liu of the Howard Hughes Medical Institute. Young Yon Kwon, Juliya Hsiang, and Sheng Hui from Harvard University’s TH Chan School of Public Health; Eileen White and Maria Gomez of Rutgers University; Alice R. Wang, Xiang Zhao, and Tobias Janowitz of Cold Spring Harbor Laboratory;
Dr. Papagiannakopoulos and New York University Langone have filed a patent application for intellectual property related to their latest research. NYU Langone governs the terms and conditions of these relationships in accordance with its policies and procedures.
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References:
Cross, M. Others. (2026). Dietary switching promotes sensory neuron-dependent cancer-associated cachexia. Science. DOI: 10.1126/science.adz4196. https://www.science.org/doi/10.1126/science.adz4196
