Description:
Abstract Melanoma is a highly aggressive skin cancer arising from transformed melanocytes. Despite tremendous efforts and considerable progress in clinical treatment, melanoma remains a deadly disease characterized by abundant treatment resistance due to high phenotype plasticity of melanoma cells. In order to evade therapy, melanoma cells can undergo phenotype switching from a differentiated state towards a dedifferentiated and more stem cell-like state. Recently, some melanoma cells with neural crest-like characteristics were shown to be able to sustain tumor growth and to give rise to distant metastases. Here, we use the technique of directed differentiation of human induced pluripotent stem cells (hiPSCs) to characterize the human neural crest cell population in vitro and to identify potential genes that are reactivated during melanoma progression. We differentiated hiPSCs towards melanocytes via the neural crest stage. Expression analyses revealed an overexpression of the Forkhead Box D1 (FOXD1) transcription factor in neural crest cells and importantly, increased FOXD1 expression was also found in melanoma cells compared to normal human melanocytes. Interestingly, in invasive and less proliferative melanoma cells, FOXD1 expression was elevated compared to highly proliferative and less motile cells, indicating a potential role of this factor in motility acquisition. To gain deeper insight into the expression pattern of FOXD1 in clinical samples, a protein expression analysis using tissue microarrays was performed determining FOXD1 expression in melanocytic nevi, primary and metastatic melanoma samples. Surprisingly, in benign melanocytic nevi, FOXD1 was dominantly localized in the nucleus whereas a shift towards a cytoplasmic localization was observed in both, primary and metastatic melanomas. Loss of FOXD1 gene in melanoma cells also revealed the importance of this gene in melanoma cell migration and invasion. Further characterization of FOXD1 and its role in melanoma progression may help to understand the phenotypic plasticity of melanoma cells, which is required for overcoming resistance in anti-melanoma therapy. In conclusion, FOXD1 is overexpressed and aberrantly localized in malignant melanoma cells compared to melanocytes. Our data indicate its function in melanoma migration and invasion. FOXD1 might be an interesting target in melanoma therapy. Citation Format: Huizi Wu, Lionel Larribere, Kasia Weina, Nathalie Knappe, Christoffer Gebhardt, Viktor Umansky, Jochen Utikal. Neural crest-like gene FOXD1 plays a role in melanoma cell migration and invasion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1277.