Multiple roles of β3-adrenergic receptor in pediatric cancers.

The β3-Adrenergic Receptor (β3-AR) is one of the β-ARs subtypes regulating various physiological responses, including thermogenesis, vasodilatation and cardiac functions, following activation mediated by catecholamines. Recently, increasing evidence demonstrated the role of β3-ARs in the tumorigenesis, growth and progression of various cancer types. Despite the efficacy of current therapies and the identification of several genes involved in the onset and growth of pediatric cancers, they remain the second leading cause of death in children. This thesis had two major aims. First, to investigate the link between β3-ARs and cancer-evoked pain and tumor metabolism in pediatric cancers. We found that the development of cancer-evoked pain is mediated by oxidative stress in a murine osteosarcoma model, associated with the recruitment of neuronal macrophages, and that the β3-ARs, but also β2-ARs, antagonism contributes to the reduction of tumor growth and cancer-associated pain. Second, to characterize the metabolic adaptation of malignant rhabdoid tumor of the kidney (MRTK) G-401 cells to nutrient deprivation to sustain cell survival. In particular, we identify that tyrosine/phenylalanine and glutamine deprivation leads to enhanced glucose metabolism, regulated by β3-ARs. These results indicating the β3-ARs as possible pharmacological targets for preventing cancer-evoked pain and metabolic compensatory mechanism that allow MRTK cell survival even during nutrient deprivation.