Fig. 4

Epidermal melanoma cells invade the dermis and undergo phenotypic switch to a neuronal-like state. a Schematic showing TAM treatment and skin implantation onto nude mice for b–h. b, c Immunofluorescence for GFP at 10 days b and 17 days c after skin implantation in c-Kit-CreER:Braf:Pten:GFP mice. Arrowheads point to GFP⁺ melanoma cells that invade into the dermis. d Immunofluorescence for GFP (green) and E-cadherin, MCAM (red) at 17 days after skin implantation in c-Kit-CreER:Braf:Pten:GFP mice. e Immunofluorescence for Sox10 (red) and E-cadherin, MCAM (green) in human melanoma specimen during the invasive radial growth phase. f, g Immunofluorescence images for GFP (green) and Dct, MITF, Nestin, GFAP, Tubb3 (red) and brightfield images in areas of dermal melanoma at 22 days f and 30 days g after skin implantation in c-Kit-CreER:Braf:Pten:GFP mice. h Dot plot showing percentage of pigment, Dct, Nestin, GFAP and Tubb3 in GFP⁺ dermal melanoma cells (mean ± s.d.; 3 independent tumors from 3 mice were analyzed in each group, n = the number of randomly selected tumor areas analyzed. At least 1500 GFP⁺ tumor cells were analyzed in each group). i Schematic model illustration showing that upon oncogenic induction, McSCs first give rise to epidermal melanoma. Then melanoma cells in the epithelial compartments invade into the dermis. Finally, dermal melanoma cells undergo a phenotypic switch to acquire neuronal signatures. j Schematic showing 4-hydroxytamoxifen (4HT-TAM) treatment and analysis regimen. k Immunofluorescence images for Tomato (red) and Sox10, Dct, Tubb3, Nestin (green) and brightfield images in c-Kit-CreER:Braf:Pten:Tomato mouse skin at 47 days. l Immunofluorescence images for Tomato (red), Dct (green) and brightfield images in lymph node of c-Kit-CreER:Braf:Pten:Tomato mouse at 47 days. m Survival graph showing the days of survival of indicated mice (n = the number of mice). Dashed line outlines the boundary of epithelium and dermis. Scale bars, 50 μm. Source data are provided as a Source Data file