BRAFV600E melanoma cells secrete factors that activate stromal fibroblasts and enhance tumourigenicity

Background: Melanoma, the most lethal form of skin cancer, is responsible for over 80% of all skin cancer deaths and is highly metastatic, readily spreading to the lymph nodes or metastasising to other organs. The frequent genetic mutation found in metastatic melanoma, BRAF(V600E), results in constitutive activation of the mitogen-activated protein kinase pathway. Methods: In this study, we utilised genetically engineered melanoma cell lines and xenograft mouse models to investigate how BRAF(V600E) affected cytokine (IL-1 beta, IL-6, and IL-8) and matrix metalloproteinase-1 (MMP-1) expression in tumour cells and in human dermal fibroblasts. Results: We found that BRAF(V600E) melanoma cells expressed higher levels of these cytokines and of MMP-1 than wild-type counterparts. Further, conditioned medium from the BRAF(V600E) melanoma cells promoted the activation of stromal fibroblasts, inducing expression of SDF-1 and its receptor CXCR4. This increase was mitigated when the conditioned medium was taken from melanoma cells treated with the BRAF(V600E) specific inhibitor, vemurafenib. Conclusions: Our findings highlight the role of BRAF(V600E) in activating the stroma and suggest a mechanistic link between BRAF(V600E) and MMP-1 in mediating melanoma progression and in activating adjacent fibroblasts in the tumour microenvironment.