| Project Detail |
Metastasis is the leading cause of death in cancer patients. Aging is an important risk factor for metastasis formation, yet the underlying processes remain poorly understood. Given the increase in aging populations worldwide, elucidating mechanisms of age-promoted metastasis formation is an important and timely topic addressed in this proposal. Recently, the Fendt group has pioneered the concept that tumor-secreted factors (TSF) induce nutrient priming of distant organs for metastasis formation. This concept is exemplified by adaptations in lipid metabolism of target organs, triggering a pro-metastatic signaling pathway in invading tumor cells. I propose that nutrient priming is age-dependent, as the metabolism changes with age, contributing to the enhanced risk of metastasis formation in the elderly. I will investigate this concept using melanoma as a prototypic cancer of age-dependent, aggressive metastatic behavior. I will address 3 specific objectives: (1) Identify age-dependent metabolic response of distant organs to TSF using mass spectrometry imaging-based spatial metabolomics in young and aging mouse models, and corroborate my findings in melanoma patients. (2) Elucidate molecular mechanisms whereby identified metabolites promote the pre-metastatic potential of the distant niche by applying genetic screens as well as multi-omics and functional assays to spheroid models of metastasis. (3) Validate the therapeutic potential of intercepting age-specific metabolic priming using pharmacological and genetic perturbations in mouse melanoma models. Ultimately, I expect to identify age-specific metabolic adaptations in pre-metastatic niches and to document that these pathways provide targets for personalized therapy of metastatic tumors in the elderly. This ambitious proposal is based on my expertise in elucidating the instructive role of metabolites in cell fate and function, and on expert skills in cancer metabolism research that I will acquire in the Fendt lab. |
