Wnt-signaling enhances neural crest migration of melanoma cells and induces an invasive phenotype

• Published in: Molecular cancer 2018-02, Vol.17 (1), p.59-59, Article 59
• Main Authors: Sinnberg, Tobias, Levesque, Mitchell P, Krochmann, Jelena, Cheng, Phil F, Ikenberg, Kristian, Meraz-Torres, Francisco, Niessner, Heike, Garbe, Claus, Busch, Christian
• Format: Article
• Language: English
• Subjects: Analysis; Animals; beta Catenin - genetics; beta Catenin - metabolism; Biomarkers; Bone morphogenetic proteins; Cancer metastasis; Cell Adhesion; Cell Movement - drug effects; Cell Movement - genetics; Cell Transformation, Neoplastic - metabolism; Chick Embryo; Disease Models, Animal; Embryonic development; Epithelial mesenchymal transition; Epithelial-Mesenchymal Transition - genetics; Gene expression; Gene Knockdown Techniques; Genetic aspects; Humans; Invasion; Melanoma; Melanoma - etiology; Melanoma - metabolism; Melanoma - mortality; Melanoma - pathology; Melanoma, Experimental; Metastasis; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neural Crest - metabolism; Neural Crest - pathology; Perylene - analogs & derivatives; Perylene - pharmacology; Phenotype; RNA, Small Interfering - genetics; Wnt Signaling Pathway; Wnt3a; Zebrafish; β-catenin
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-018-0773-5

During embryonic development Wnt family members and bone morphogenetic proteins (BMPs) cooperatively induce epithelial-mesenchymal transition (EMT) in the neural crest. Wnt and BMPs are reactivated during malignant transformation in melanoma. We previously demonstrated that the BMP-antagonist noggin blocked the EMT phenotype of melanoma cells in the neural crest and malignant invasion of melanoma cells in the chick embryo; vice-versa, malignant invasion was induced in human melanocytes in vivo by pre-treatment with BMP-2. Although there are conflicting results in the literature about the role of β-catenin for invasion of melanoma cells, we found Wnt/β-catenin signaling to be analogously important for the EMT-like phenotype of human metastatic melanoma cells in the neural crest and during invasion: β-catenin was frequently expressed at the invasive front of human primary melanomas and Wnt3a expression was inversely correlated with survival of melanoma patients. Accordingly, cytoplasmic β-catenin levels were increased during invasion of melanoma cells in the rhombencephalon of the chick embryo. Fibroblast derived Wnt3a reduced melanoma cell adhesion and enhanced migration, while the β-catenin inhibitor PKF115-584 increased adhesion and reduced migration in vitro and in the chick embryonic neural crest environment in vivo. Similarly, knockdown of β-catenin impaired intradermal melanoma cell invasion and PKF115-584 efficiently reduced liver metastasis in a chick chorioallantoic membrane model. Our observations were accompanied by specific alterations in gene expression which are linked to overall survival of melanoma patients. We present a novel role for Wnt-signaling in neural crest like melanoma cell invasion and metastasis, stressing the crucial role of embryonic EMT-inducing neural crest signaling for the spreading of malignant melanoma.