The aging microenvironment promotes melanoma cell invasion and therapy resistance. Homo sapiens

Cancer is a disease of aging, and incidence and mortality from all cancers increase logarithmically after the age of 45. Older patients have a much poorer prognosis for melanomas of equal stage, compared to younger individuals. The role of the tumor microenvironment in modulating cancer behavior is widely recognized. We hypothesized that age-related changes in the tumor microenvironment could affect the progression of melanoma. We demonstrate that the aging microenvironment increases the invasion of melanoma cells. Using skin fibroblasts isolated from healthy donors, we have built artificial skin and demonstrate that melanoma cells invade more rapidly when exposed to aged fibroblasts. In a mouse model of melanoma (YUMM1.7, BrafV600E/Cdkn2a-/-/Pten-/-), congeneic to C57/BL6 mice, melanomas invade faster in aged mice. Gene expression analyses suggest that melanoma cells are undergoing DNA damage when exposed to an aged microenvironment, and we confirm this in cellular assays. Proteomics analysis of aging fibroblasts suggest that fibroblasts secrete molecules (laminin b2, Wnt inhibitors) associated with increased resistance to targeted therapy. Indeed, melanoma cells injected into aged mice respond less well to PLX4720 than those injected into young mice. This suggests that exciting new drugs targeting the BRAF pathway may be less effective in aging patients. Overall design: To assess the effects of the aging microenvironment on melanoma cell gene expression, we co-cultured dermal fibroblasts from young (55 years) individuals with three different melanoma cell lines (UACC1273, M93-047 and UACC903) in triplicate using transwell chambers. After 96 h of co-culture, fibroblasts in the upper well were removed, and melanoma cells (lower chamber) were subjected to microarray analysis.