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


ABSTRACT: BACKGROUND: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. RESULTS:Although there are conflicting results in the literature about the role of ?-catenin for invasion of melanoma cells, we found Wnt/?-catenin signaling to be analogously important for the EMT-like phenotype of human metastatic melanoma cells in the neural crest and during invasion: ?-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 ?-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 ?-catenin inhibitor PKF115-584 increased adhesion and reduced migration in vitro and in the chick embryonic neural crest environment in vivo. Similarly, knockdown of ?-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. CONCLUSION: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.

SUBMITTER: Sinnberg T 

PROVIDER: S-EPMC5816360 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Sinnberg Tobias T   Levesque Mitchell P MP   Krochmann Jelena J   Cheng Phil F PF   Ikenberg Kristian K   Meraz-Torres Francisco F   Niessner Heike H   Garbe Claus C   Busch Christian C  

Molecular cancer 20180217 1


<h4>Background</h4>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 me  ...[more]

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