Senescent Fibroblasts Drive Melanoma Progression Through GCP-2 Induced CREB Phosphorylation Enhancing Glycolysis

Aging constitutes the largest risk factor for melanoma progression. While a contribution of factors secreted from senescent skin fibroblasts to the progression of melanoma has been proposed, the nature of such factors and subsequent underlying mechanisms remains elusive. Here we show that the chemokine GCP-2 is excessively released by senescent fibroblasts in vitro and the skin of old melanoma patients. GCP-2 regulates, via phosphorylation of the transcription factor CREB at serine 133, defense-, cell cycle control-, and glycolysis-enhancing genes in melanoma cell lines. GCP-2 promotes oncogenic properties in vitro and in vivo in murine melanoma models. Inhibition of CREB phosphorylation in melanoma cells represses glycolytic target genes and induces a switch from glycolysis to oxidative phosphorylation that translates into a significant decline in tumor size in vivo in murine melanoma models. This study identifies a senescent fibroblast to chemokine to CREB to metabolic axis that drives melanoma progression. Targeting this axis may hold promise for novel therapeutic approaches in difficult-to-treat melanoma in older adults.