PUBLICATION
Wnt-signaling enhances neural crest migration of melanoma cells and induces an invasive phenotype
- Authors
- Sinnberg, T., Levesque, M.P., Krochmann, J., Cheng, P.F., Ikenberg, K., Meraz-Torres, F., Niessner, H., Garbe, C., Busch, C.
- ID
- ZDB-PUB-190117-9
- Date
- 2018
- Source
- Molecular Cancer 17: 59 (Journal)
- Registered Authors
- Keywords
- Epithelial mesenchymal transition, Invasion, Melanoma, Metastasis, Wnt3a, β-catenin
- MeSH Terms
-
- Animals
- Biomarkers
- Cell Adhesion
- Cell Movement*/drug effects
- Cell Movement*/genetics
- Cell Transformation, Neoplastic/metabolism*
- Chick Embryo
- Disease Models, Animal
- Epithelial-Mesenchymal Transition/genetics
- Gene Knockdown Techniques
- Humans
- Melanoma/etiology*
- Melanoma/metabolism*
- Melanoma/mortality
- Melanoma/pathology
- Melanoma, Experimental
- Mice
- Neoplasm Invasiveness
- Neoplasm Metastasis
- Neural Crest/metabolism*
- Neural Crest/pathology
- Perylene/analogs & derivatives
- Perylene/pharmacology
- Phenotype*
- RNA, Small Interfering/genetics
- Wnt Signaling Pathway*
- Zebrafish
- beta Catenin/genetics
- beta Catenin/metabolism
- PubMed
- 29454361 Full text @ Mol. Cancer
Citation
Sinnberg, T., Levesque, M.P., Krochmann, J., Cheng, P.F., Ikenberg, K., Meraz-Torres, F., Niessner, H., Garbe, C., Busch, C. (2018) Wnt-signaling enhances neural crest migration of melanoma cells and induces an invasive phenotype. Molecular Cancer. 17:59.
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 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.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping