A dietary switch promotes sensory neuron–dependent cancer-associated cachexia.
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| Title: | A dietary switch promotes sensory neuron–dependent cancer-associated cachexia. |
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| Authors: | Cross, Michael (AUTHOR), Kotschi, Stefan (AUTHOR), Wu, Warren (AUTHOR), Luciano-Mateo, Fedra (AUTHOR), Kwon, Young-Yon (AUTHOR), Dantas, Ezequiel (AUTHOR), Niazi, Taha (AUTHOR), Chen, Shijia (AUTHOR), Rashidfarrokhi, Ali (AUTHOR), Pillai, Ray (AUTHOR), Sanford, Jack (AUTHOR), Kim, Jeshua (AUTHOR), Hsiang, Juliya (AUTHOR), Gamallo-Lana, Begona (AUTHOR), Mar, Adam C. (AUTHOR), Hao, Yuan (AUTHOR), Rajalingam, Sahith (AUTHOR), Huang, Annie (AUTHOR), Shan, Jackie (AUTHOR), Issa, Habon A. (AUTHOR) |
| Source: | Science. 7/2/2026, Vol. 393 Issue 6806, p90-97. 8p. |
| Subjects: | Cachexia, Prostaglandins, Lung cancer, Peripheral nervous system, Cell communication, High-fat diet, Sensory neurons |
| Abstract: | Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE2), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE2 suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE2-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia. Editor's summary: Cancer cachexia is a complex metabolic syndrome marked by reduced appetite, weight loss, and muscle wasting. Cross et al. report that a subset of Lkb1-mutant lung cancers is prone to cachexia (see the Perspective by Gültekin and Vander Heiden). When mice were fed a high-calorie, high-fat diet, reduced appetite and weight loss were observed, which was associated with reduced appetite sensing to the brain. Prostaglandin E2 (PGE2) is a lipid-signaling molecule produced by tumors that increases when animals consume fat. The authors found that PGE2 acts locally in the lung to drive decreased weight and appetite. Blocking either PGE2 production or silencing sensory nerves reduced cachexia, suggesting that the peripheral nervous system may represent a therapeutic target. The observations further suggest that tumors can trigger cachexia through local nerve signaling, as opposed to only circulating factors. —Priscilla N. Kelly [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE2), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE2 suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE2-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia. Editor's summary: Cancer cachexia is a complex metabolic syndrome marked by reduced appetite, weight loss, and muscle wasting. Cross et al. report that a subset of Lkb1-mutant lung cancers is prone to cachexia (see the Perspective by Gültekin and Vander Heiden). When mice were fed a high-calorie, high-fat diet, reduced appetite and weight loss were observed, which was associated with reduced appetite sensing to the brain. Prostaglandin E2 (PGE2) is a lipid-signaling molecule produced by tumors that increases when animals consume fat. The authors found that PGE2 acts locally in the lung to drive decreased weight and appetite. Blocking either PGE2 production or silencing sensory nerves reduced cachexia, suggesting that the peripheral nervous system may represent a therapeutic target. The observations further suggest that tumors can trigger cachexia through local nerve signaling, as opposed to only circulating factors. —Priscilla N. Kelly [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adz4196 |
