1. Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice
- Author
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Van Phung, Higbee Jared Martin, Marilyn Wang, Rowena Suriben, Yan Wang, Dina A. Ayupova, Diana Li, Hung-I Harry Chen, Subhash D. Katewa, André O. White, Zhengyu Gao, Michele McEntee, Andrea Olland, Damodharan Lakshminarasimhan, Richard Ventura, Michael Chen, Julie Oeffinger, Jie Tang, Shelley R. Starck, Jer-Yuan Hsu, Darrin A. Lindhout, Pranali Taskar, Kalyani Mondal, Mark J. Solloway, Raj Haldankar, Avantika Kekatpure, Bernard B. Allan, and Betty Chan Li
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cachexia ,Glial Cell Line-Derived Neurotrophic Factor Receptors ,Growth Differentiation Factor 15 ,Adipose tissue ,Crystallography, X-Ray ,Proto-Oncogene Mas ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Lipid oxidation ,Weight loss ,Internal medicine ,Cell Line, Tumor ,Neoplasms ,Weight Loss ,medicine ,Glial cell line-derived neurotrophic factor ,Animals ,Humans ,Muscle, Skeletal ,biology ,business.industry ,Proto-Oncogene Proteins c-ret ,Skeletal muscle ,Antibodies, Monoclonal ,Lipid metabolism ,General Medicine ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Adipose Tissue ,030220 oncology & carcinogenesis ,Multiprotein Complexes ,Adipose triglyceride lipase ,biology.protein ,Heterografts ,Lipid Peroxidation ,medicine.symptom ,business ,Signal Transduction - Abstract
Cancer cachexia is a highly prevalent condition associated with poor quality of life and reduced survival1. Tumor-induced perturbations in the endocrine, immune and nervous systems drive anorexia and catabolic changes in adipose tissue and skeletal muscle, hallmarks of cancer cachexia2-4. However, the molecular mechanisms driving cachexia remain poorly defined, and there are currently no approved drugs for the condition. Elevation in circulating growth differentiation factor 15 (GDF15) correlates with cachexia and reduced survival in patients with cancer5-8, and a GDNF family receptor alpha like (GFRAL)-Ret proto-oncogene (RET) signaling complex in brainstem neurons that mediates GDF15-induced weight loss in mice has recently been described9-12. Here we report a therapeutic antagonistic monoclonal antibody, 3P10, that targets GFRAL and inhibits RET signaling by preventing the GDF15-driven interaction of RET with GFRAL on the cell surface. Treatment with 3P10 reverses excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia, even under calorie-restricted conditions. Mechanistically, activation of the GFRAL-RET pathway induces expression of genes involved in lipid metabolism in adipose tissues, and both peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from GDF15-induced weight loss. These data uncover a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue independently of anorexia, leading to reduced adipose and muscle mass and function in tumor-bearing mice.
- Published
- 2020