Abstract 3640: Adipocyte age dependent metabolic programming dictates melanoma metastatic burden and tropism

Abstract

Abstract The aged skin microenvironment and aged fibroblasts contribute to melanoma progression. A key hallmark of skin ageing is the loss of subcutaneous fat. Because previous work has established that lipids contribute to melanoma invasion and proliferation, we studied whether aged adipocytes contribute to the poor outcome of aged patients. We compared the distinct lipid secretory profile of young and aged human subcutaneous adipocytes, and discovered young and aged adipocytes contribute different lipids to the melanoma microenvironment, activating aged-dependent signaling pathways and driving distinct metabolic programms in melanoma cells. To test how aged and young adipocytes affect melanoma, we obtained human preadipocytes from donors of different ages and differentiated them to functional adipocytes in vitro. We studied the morphological, transcriptomic, proteomic, and lipid profile of adipocytes by age, then exposed melanoma cells to the young or aged adipocyte secretome. We observed melanoma cells exposed to young adipocyte secretome increased the rate of proliferation, invasion, and migration compared to melanoma cells exposed to aged adipocyte secretomes. This effect was linked to a greater amount of total lipids secreted by young adipocytes, as well as a unique ratio of lipids by age, which were taken up by melanoma cells. Critically, lipid transfer led to distinct signaling pathway activation and metabolic reprogramming. In vivo, these differences led to a greater rate of metastasis and distinct tropism of melanoma cells exposed to aged or young adipocyte secretomes. Finally, we systematically tested the contribution of differentially secreted lipids by age and identified the specific lipids that function as signaling molecules to switch metabolic dependencies and fuel proliferation, invasion, and migration of melanoma cells Citation Format: Shilpa Gurung. Adipocyte age dependent metabolic programming dictates melanoma metastatic burden and tropism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3640.