Age-dependent nutrient priming of the pre-metastatic niche

Descrizione del progetto

L’invecchiamento e il modo in cui alimenta le metastasi

Con l’invecchiamento, il nostro metabolismo e il microambiente tissutale subiscono profondi cambiamenti che alterano il modo in cui le cellule rispondono allo stress e alle malattie, variazioni metaboliche legate all’età che possono influenzare la progressione del cancro, in particolare la diffusione dei tumori a organi distanti. Poiché le metastasi restano la principale causa di mortalità per cancro, la comprensione del modo in cui l’invecchiamento favorisce questo processo è essenziale. Sostenuto dal programma di azioni Marie Skłodowska-Curie, il progetto PrimeAge esplorerà il modo in cui i fattori secreti dai tumori inducono un priming metabolico dei nutrienti dipendente dall’età in organi distanti, favorendo la formazione di metastasi. Utilizzando il melanoma come modello, il progetto combinerà la metabolomica spaziale e le analisi multinomiche al fine di identificare e indirizzare i percorsi metabolici specifici per età, aprendo la strada allo sviluppo di interventi personalizzati contro la metastasi.

Obiettivo

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.