Fig. 8: Analysis of the invasive front of human metastatic melanomas.

a–i Representative images (left) and quantification (right) of a melanoma cell shape score, b H-score of p-MLC2 staining, c ki-67 positive cells, H-score of d DAAM1, e WNT11, f WNT5B, g ALDH1A1, h CD44 and i NANOG staining in matched TB and IF from melanoma metastases. j Model summarizing the findings of this study. The IF of human primary melanomas is enriched in cells with rounded-amoeboid morphology, high levels of Myosin II, proliferative, non-canonical Wnt and cancer stem cell-related markers. This phenotype is recapitulated and further enriched in melanoma metastasis. WNT11/5B activate FZD7 and DAAM1 to control Rho activity and then ROCK1/2-Myosin II levels. All these signalling components have an impact on amoeboid features and tumour initiation in melanoma both in vitro and in vivo. Specifically, DAAM1 plays an essential role in tumour and metastasis initiation and subsequent metastatic outgrowth by sustaining the amoeboid phenotype. a–i 45 metastatic melanomas. a, e–i Scale bar, 100 μm; inset, 50 μm. b–d Scale bar, 300 μm. a–i Box limits show 25th and 75th percentiles, the horizontal line shows the median, and whiskers show minimum and maximum range of values. a, b, d–f Two-tailed paired t-test. c, g–i Two-tailed Wilcoxon test. Human schematic in this figure was created using Servier Medical Art templates licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com).