A dietary switch promotes sensory neuron-dependent cancer-associated cachexia

• 成果类型: Article
• 署名作者: Cross, Michael; Kotschi, Stefan; Wu, Warren; Luciano-Mateo, Fedra; Kwon, Young-Yon; Dantas, Ezequiel; Niazi, Taha; Chen, Shijia; Rashidfarrokhi, Ali; Pillai, Ray; Sanford, Jack; Kim, Jeshua; Hsiang, Juliya; Gamallo-Lana, Begona; Mar, Adam C.; Hao, Yuan; Rajalingam, Sahith; Huang, Annie; Shan, Jackie; Issa, Habon A.; Gomez, Maria; Wang, Alice R.; Zhao, Xiang; Janowitz, Tobias; White, Eileen; Liu, Yin; Wong, Kwok-Kin; Segal, Leopoldo N.; Hui, Sheng; Goncalves, Marcus D.; Froemke, Robert C.; Papagiannakopoulos, Thales
• 署名单位: New York University; Harvard University; Harvard T.H. Chan School of Public Health; New York University; New York University; New York University; New York University; Rutgers University System; Rutgers University New Brunswick; Rutgers University Biomedical & Health Sciences; Rutgers Cancer Institute of New Jersey; Rutgers University System; Rutgers University New Brunswick; Ludwig Institute for Cancer Research; Princeton University; Cold Spring Harbor Laboratory; State University of New York (SUNY) System; Stony Brook University; State University of New York (SUNY) System; Stony Brook University; Northwell Health; Howard Hughes Medical Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adz4196
• 发表日期: 2026-07-02
• 页码: 90-97
• 关键词: cooccurring genomic alterations; LUNG ADENOCARCINOMA; weight-loss; tumor; cytokine; receptor; mice; ANOREXIA; protein; gdf15

摘要

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.