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.

Automated summary

Obesity is associated with the occurrence and development of melanoma. The mechanism involves the downregulation of p16(INK4A) expression in melanoma cells by adipocytes through beta-catenin-dependent regulation, which increases cell motility. Adipocytes from individuals with obesity secrete a larger number of vesicles, delivering more beta-catenin to melanoma cells.