Adipocyte Extracellular Vesicles Decrease p16INK4A in Melanoma: An Additional Link between Obesity and Cancer

Obesity is a recognized factor for increased risk and poor prognosis of many cancers, including melanoma. In this study, using genetically engineered mouse models of melanoma (Nras(Q61K) transgenic expression, associ-ated or not with Cdkn2a heterozygous deletion), we show that obesity increases melanoma initiation and progression by supporting tumor growth and metastasis, thereby reducing survival. This effect is associated with a decrease in p16(INK4A) expression in tumors. Mechanistically, adipocytes downregulate p16(INK4A) in mel-anoma cells through beta-catenin-dependent regulation, which increases cell motility. Furthermore, beta-catenin is directly transferred from adipocytes to melanoma cells in extracellular vesicles, thus increasing its level and activity, which represses CDKN2A transcription. Adipocytes from individuals with obesity have a stronger effect than those from lean individuals, mainly owing to an increase in the number of vesicles secreted, thus increasing the amount of beta-catenin delivered to melanoma cells and, consequently, amplifying their effect. In conclusion, in this study, we reveal that adipocyte extracellular vesicles control p16(INK4A) expression in mela-noma, which promotes tumor progression. This work expands our understanding of the cooperation between adipocytes and tumors, particularly in obesity.