Adipocyte Extracellular Vesicles Decrease p16INK4A in Melanoma: An Additional Link between Obesity and Cancer.
J Invest Dermatol
; 142(9): 2488-2498.e8, 2022 09.
Article
en En
| MEDLINE
| ID: mdl-35150661
ABSTRACT
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 (NrasQ61K transgenic expression, associated 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 p16INK4A expression in tumors. Mechanistically, adipocytes downregulate p16INK4A in melanoma cells through ß-catenin-dependent regulation, which increases cell motility. Furthermore, ß-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 ß-catenin delivered to melanoma cells and, consequently, amplifying their effect. In conclusion, in this study, we reveal that adipocyte extracellular vesicles control p16INK4A expression in melanoma, which promotes tumor progression. This work expands our understanding of the cooperation between adipocytes and tumors, particularly in obesity.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Inhibidor p16 de la Quinasa Dependiente de Ciclina
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Vesículas Extracelulares
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Melanoma
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Obesidad
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Invest Dermatol
Año:
2022
Tipo del documento:
Article
País de afiliación:
Francia