A dietary switch promotes sensory neuron–dependent cancer-associated cachexia
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 (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.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (32)
Michael Cross
Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
Stefan Kotschi
Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
Warren Wu
Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
Fedra Luciano-Mateo
Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
Young-Yon Kwon
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Ezequiel Dantas
Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
Taha Niazi
Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
Shijia Chen
Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
Ali Rashidfarrokhi
Ray Pillai
Jack Sanford
Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
Jeshua Kim
Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
Juliya Hsiang
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Begoña Gamallo-Lana
Adam C. Mar
Yuan Hao
Sahith Rajalingam
Annie Huang
Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
Jackie Shan
Department of Neuroscience, New York University Grossman School of Medicine, New York, NY, USA.
Habon A. Issa
Department of Neuroscience, New York University Grossman School of Medicine, New York, NY, USA.
Maria Gomez
Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ, USA.
Alice R. Wang
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Xiang Zhao
Tobias Janowitz
Eileen White
Yin Liu
Kwok-Kin Wong
Leopoldo N. Segal
Division of Pulmonary, Critical Care, and Sleep Medicine, New York University Grossman School of Medicine, New York, NY, USA.
Sheng Hui
Marcus D. Goncalves
Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
Robert C. Froemke
Thales Papagiannakopoulos