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The aging microenvironment promotes melanoma cell invasion and therapy resistance

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57445 | GEO | 2016/04/08

SECONDARY ACCESSION(S): PRJNA246469

REPOSITORIES: GEO

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Project description:Fifty percent of cutaneous melanomas are driven by activated BRAFV600E, but tumors treated with RAF inhibitors, even when they respond dramatically, rapidly adapt and develop resistance. Thus, there is a pressing need to identify the major mechanisms of intrinsic and adaptive resistance and develop drug combinations that target these resistance mechanisms. In a combinatorial drug screen on a panel of 12 treatment-naïve BRAFV600E mutant melanoma cell lines of varying levels of resistance to MAPK pathway inhibition we identified the combination PLX4720, a targeted inhibitor of mutated BRaf, and lapatinib, an inhibitor of the ERBB family of receptor tyrosine kinases, as synergistically cytotoxic in the subset of cell lines that displayed the most resistance to PLX4720. To identify potential mechanisms of resistance to PLX4720 treatment and synergy with lapatinib treatment we performed a multi-platform functional genomics analysis to profile the genome as well as the transcriptional and proteomic responses of these cell lines to treatment with PLX4720. We found modest levels of resistance correlated with the zygosity of the BRAF V600E allele and RTK mutational status. Layered over base-line resistance was substantial upregulation of many ERBB pathway genes in response to BRaf inhibition, thus generating the vulnerability to combination with lapatinib. The transcriptional responses of ERBB pathway genes are associated with a number of transcription factors, including ETS2 and its associated cofactors that represent a convergent regulatory mechanism conferring synergistic drug susceptibility in the context of diverse mutational landscapes. 12 BRAF mutant melanomas and 4 melanomas with WT BRAF were exposed plx4720 treatment to evaluate their responses after 8 hours of treatment. 5 of the 12 BRAF mutant melanomas responses were also evaluated in response to the treatment of lapatinib alone, masitinib alone, the combination of lapatinib with plx4720, or the combination of masitinib with plx4720. All samples were run in at least triplicate.

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The aging microenvironment promotes melanoma cell invasion and therapy resistance

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