RESUMEN
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.
Asunto(s)
Caquexia/tratamiento farmacológico , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor 15 de Diferenciación de Crecimiento/genética , Complejos Multiproteicos/ultraestructura , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-ret/genética , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Anticuerpos Monoclonales , Caquexia/complicaciones , Caquexia/genética , Caquexia/inmunología , Línea Celular Tumoral , Cristalografía por Rayos X , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/ultraestructura , Factor 15 de Diferenciación de Crecimiento/ultraestructura , Xenoinjertos , Humanos , Peroxidación de Lípido , Ratones , Complejos Multiproteicos/genética , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Neoplasias/complicaciones , Neoplasias/genética , Neoplasias/inmunología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-ret/ultraestructura , Transducción de Señal , Pérdida de PesoRESUMEN
Signaling through the receptor tyrosine kinase RET is essential during normal development. Both gain- and loss-of-function mutations are involved in a variety of diseases, yet the molecular details of receptor activation have remained elusive. We have reconstituted the complete extracellular region of the RET signaling complex together with Neurturin (NRTN) and GFRα2 and determined its structure at 5.7-Å resolution by cryo-EM. The proteins form an assembly through RET-GFRα2 and RET-NRTN interfaces. Two key interaction points required for RET extracellular domain binding were observed: (i) the calcium-binding site in RET that contacts GFRα2 domain 3 and (ii) the RET cysteine-rich domain interaction with NRTN. The structure highlights the importance of the RET cysteine-rich domain and allows proposition of a model to explain how complex formation leads to RET receptor dimerization and its activation. This provides a framework for targeting RET activity and for further exploration of mechanisms underlying neurological diseases.