Study Reveals How Lung Tumors "Hack" into Nervous System to Starve the Body

NEW YORK, July 9, 2026 /PRNewswire/ -- Cachexia is a condition in which patients affected by cancer or other chronic diseases become sick and lose weight. The condition often involves brain-related symptoms of sickness, such as loss of appetite, which can lead to loss of muscle and often fat. Because this wasting condition can make patients too frail to tolerate treatments or to be eligible for clinical trials, researchers say many patients ultimately succumb to cachexia instead of cancer.

Despite this toll, cachexia is not well understood, and efforts to treat it have largely been unsuccessful. Now, a new study led by researchers at NYU Langone Health and its Perlmutter Cancer Center reveals a new cachexia-causing pathway linked to lung cancer that may, if further experiments prove successful, point to improved treatments.

"Our research shows that tumors can cause cachexia by essentially hacking into the nervous system and altering eating behavior," said study senior investigator Thales Y. Papagiannakopoulos, PhD, an associate professor in the Department of Pathology at NYU Grossman School of Medicine and a member of Perlmutter Cancer Center. "Many groups have studied how molecules circulating throughout the body during chronic disease cause systemic effects in organs like the brain and in muscle. But our work shows that short-range communications, between tumors and nearby cells, called neurons (that are connected to the brain), can cause sickness and cachexia."

Published in the journal Science online July 2, the study established three different genetic mouse models of lung cancer. Each of the three groups was engineered to have changes in their DNA code (variants) that resembled the patterns seen in major subtypes of human lung cancer. Only the variant that was missing a gene called LKB1, however, caused cachexia in the mice. This variant did not cause bigger or more numerous tumors than the other variants, which made the researchers wonder if the LKB1-deficient tumors were producing something the others were not.

Because mice with LKB1-deficient tumors lost both fat and muscle mass due to reduced appetite, the researchers switched the mice in all three groups to a high-calorie, high-fat diet in an attempt to slow their weight loss. The mice with the subtypes of lung cancer that did not lead to cachexia quickly began gaining weight on the high-fat diet. But the researchers were surprised to see that those on the high-fat diet with inactive LKB1 in their tumors ate even less, lost even more weight, and began to die sooner than those on the original diet.

To understand how the high-fat diet was making cachexia worse, the researchers collected fluid from the tumor-filled lungs of mice with LKB1-deficient tumors and measured levels of signaling molecules that they believed may be causing cachexia. Compared with the LKB1-deficient cancer mice on the normal diet, those on the high-fat diet had much higher levels of prostaglandin E2, a signaling molecule known to amplify inflammation, the influx of immune cells to sites of injury. Over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen counter pain and swelling by blocking the action of the enzymes that make prostaglandin E2.

Even on the normal diet, the mice without active LKB1 in their tumors had significantly higher prostaglandin E2 than the mice with the other tumor variants, indicating that prostaglandin E2 was the cachexia-causing substance the LKB1-deficient tumors were producing. When the researchers blocked prostaglandin E2 production, either genetically, with NSAIDs, or with a fish oil diet rich in anti-inflammatory omega-3 fatty acids, the mice had improved survival and lost less weight, even when they were on the high-fat diet.

Since prostaglandin E2 was only elevated in lung fluid and not in the bloodstream, the team hypothesized that it was likely exerting its cachexia-causing effects locally in the lungs. Recent studies have shown that in lung infections, sickness and loss of appetite can be mediated by local prostaglandin E2 signals to lung neurons, which can then transmit signals from the lungs to the brain via the vagus nerve. The team blocked the ability of the vagus nerve to signal the brain by either surgically cutting or genetically suppressing the vagus nerve. They observed that blocking vagus nerve signaling made animals with cancer eat more, preventing the common symptom of cachexia. This confirmed that prostaglandin E2 signaling, just like in lung infections, could be communicating through lung neurons that are part of the vagus nerve and that act on the brain to affect eating behavior.

While their study was mostly in mouse models, the researchers also looked at lung fluid from human lung cancer patients. They found that prostaglandin E2 was significantly higher in patients with cachexia, suggesting that it could play a similar role in humans and that interfering with prostaglandin E2 production or signaling could improve outcomes in human patients with cachexia.

"Even though blocking prostaglandin E2 did not shrink the tumors, it made the mice stronger and more able to tolerate the toll lung cancer was taking on their bodies," said Dr. Papagiannakopoulos. "We hope our research illuminates ways to treat cachexia by blocking harmful signals to the vagus nerve and dietary interventions, so we can help patients be as strong as possible as they fight cancer."

This research forms part of the work of team CANCAN, an international team funded through Cancer Grand Challenges, a global initiative co-founded by Cancer Research UK and the National Cancer Institute. Team CANCAN brings together researchers across disciplines to uncover the biological mechanisms that drive cancer cachexia and identify new opportunities to improve outcomes for people living with cancer.

Moving forward, Dr. Papagiannakopoulos said that he and his Cancer Grand Challenge collaborators want to continue exploring the role neuronal signaling plays in cachexia and other aspects of cancer.

Funding support for the study was provided 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 the German Research Foundation grant KO 7112/1-1, as well as 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-first authors Michael Cross and Stefan Kotschi, as well as Warren Wu, Fedra Luciano-Mateo, Ezequiel Dantas, Taha Niazi, Shijia Chen, Ali Rashidfarrokhi, Ray Pillai, Jack Sanford, Jeshua Kim, Begona Gammallo-Lana, Adam C. Mar, Yuan Hao, Sahith Rajalingam, Annie Huang, Jackie Shan, Habon A. Issa, Kwok-Kin Wong, Leopoldo N. Segal, Marcus D. Goncalves, and Robert C.Froemke.

Other study co-investigators include Yin Liu at the Howard Hughes Medical Institute; Young Yon Kwon, Juliya Hsiang, and Sheng Hui at the Harvard T.H. Chan School of Public Health; Eileen White and Maria Gomez at Rutgers University; Alice R. Wang, Xiang Zhao, and Tobias Janowitz at Cold Spring Harbor Laboratory.

Dr. Papagiannakopoulos and NYU Langone have applied to patent intellectual property related to their latest research. NYU Langone is managing the terms and conditions of these relationships in accordance with its policies and procedures.

About NYU Langone Health
NYU Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient Inc. has ranked NYU Langone No. 1 out of 118 comprehensive academic medical centers across the nation for four years in a row, and U.S. News & World Report recently ranked four of its clinical specialties No. 1 in the nation. NYU Langone offers a comprehensive range of medical services with one high standard of care across seven inpatient locations, its Perlmutter Cancer Center, and more than 330 outpatient locations in the New York area and Florida. The system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.

Media Contact
David March
[email protected]
212-404-3528

STUDY DOI
10.1126/science.adz4196

SOURCE NYU Langone Health System