Remodelling of the skin stromal niche during melanoma transformation

Skin melanocytes are repeatedly exposed to ultraviolet (UV) radiation making them susceptible to somatic mutations1. Thus 80% of benign melanocytic nevi have somatic mutations in the MAPK pathway genes most commonly affecting the BRAF and NRAS oncogenes 1,2. However, far from all benign nevi transforms into an invasive melanoma. Interaction between mutant melanocytes and their skin microenvironment presumably play a key role in cancer susceptibility. Here we show that the skin microenvironmental niche is remodelled at the most incipient stage of melanoma transformation. Analysis at single cell resolution of unique tissue biopsies from patients with clinically equivocal cutaneous melanocytic lesions were included. The main variation of the global transcriptional space across a high number of melanocytic lesions representing the full clinical spectrum defined an immune response signature that was significantly correlated with the number of chromosomal alterations and histopathological diagnosis. Single cell RNA sequencing analysis revealed that in particular interferon alpha (IFN-A) signalling was altered in multiple cell types already at the intermediate stage of melanocytic transformation. Keratinocytes in close proximity to highly atypical melanocytes had an inflamed phenotype expressing IFN-inducing genes as well as S100A8/9 and communicated with and recruited macrophages and T cells. Stimulated fibroblasts localized beneath the atypical melanocytic cells were marked by tenascin-c expression, and in invasive melanomas such fibroblasts formed an immunosuppressive cellular niche spatially located as a layer between activated lymphocytes and the melanoma cells. We propose a model where the skin microenvironment is remodelled early in melanoma transformation and is crucial for melanomas to persist and progress towards advanced stage.