A dietary switch promotes sensory neuron–dependent cancer-associated cachexia
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 (PGE 2 ), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE 2 suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE 2 -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.
Authors
- Leopoldo N. Segal (ORCID: https://orcid.org/0000-0003-3559-9431)
- Jackie Shan
- Marcus DaSilva Goncalves (ORCID: https://orcid.org/0000-0002-0784-9248)
- S. Chen
- Kwok‐Kin Wong (ORCID: https://orcid.org/0000-0001-6323-235X)
- Young‐Yon Kwon (ORCID: https://orcid.org/0000-0003-1472-5726)
- Xiang Zhao (ORCID: https://orcid.org/0000-0003-3067-3970)
- Adam C. Mar (ORCID: https://orcid.org/0000-0002-2095-2936)
- Stefan Kotschi (ORCID: https://orcid.org/0000-0001-9857-6291)
- Robert C. Froemke (ORCID: https://orcid.org/0000-0002-1230-6811)
- Jack D. Sanford (ORCID: https://orcid.org/0000-0001-6054-9685)
- Yin Liu (ORCID: https://orcid.org/0000-0002-2377-2703)
- Begona Gamallo‐Lana (ORCID: https://orcid.org/0009-0004-5687-5778)
- Shih Ming Huang (ORCID: https://orcid.org/0000-0002-5070-1732)
- Michael Cross (ORCID: https://orcid.org/0000-0002-2446-9167)
- Sheng Hui (ORCID: https://orcid.org/0000-0002-4226-6806)
- Ray Pillai (ORCID: https://orcid.org/0000-0002-8335-3463)
- Sahith Rajalingam (ORCID: https://orcid.org/0000-0003-3669-3729)
- Ezequiel Dantas (ORCID: https://orcid.org/0000-0003-4934-4632)
- Thales Papagiannakopoulos (ORCID: https://orcid.org/0000-0002-2251-1624)
- Fedra Luciano‐Mateo (ORCID: https://orcid.org/0000-0002-8736-2455)
- Tobias Janowitz (ORCID: https://orcid.org/0000-0002-7820-3727)
- Eileen White (ORCID: https://orcid.org/0000-0003-2961-3065)
- Habon A. Issa (ORCID: https://orcid.org/0000-0001-7904-1582)
- Maria Gomez-Jenkins (ORCID: https://orcid.org/0000-0003-3682-9219)
- Yuan Hao (ORCID: https://orcid.org/0000-0002-4031-7868)
- Ali Rashidfarrokhi (ORCID: https://orcid.org/0000-0001-7458-7607)
- Juliya Hsiang
- Alice Wang (ORCID: https://orcid.org/0000-0003-1771-2103)
- Warren Wu
- Jeshua Kim
- Taha Niazi (ORCID: https://orcid.org/0009-0006-2747-9092)
Institutions
- Rutgers, The State University of New Jersey (US)
- Northwell Health (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Janelia Research Campus (US)
- Princeton University (US)
- Cold Spring Harbor Laboratory (US)
- VA NY Harbor Healthcare System (US)
- Rutgers Sexual and Reproductive Health and Rights (NL)
- Ludwig Cancer Research (US)
- New York University (US)
- Stony Brook University (US)
Publication Details
- Journal
- Science
- Published
- 2026-07-02
- DOI
- https://doi.org/10.1126/science.adz4196
- Citations
- 1
- Primary Topic
- Nutrition and Health in Aging
- Type
- article
- Field-Weighted Citation Impact
- 9.39
Funders
- American Cancer Society
- Pfizer
- Cancer Research UK
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- School of Medicine, New York University
- National Cancer Institute
- National Center for Research Resources