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Purpose: Melanoma tumors are highly heterogeneous and can undergo phenotypic modifications depending on their plasticity and the microenvironment, with shifts between proliferative and invasive states. We have shown that melanoma cells, grown as spheroids in a neural crest cell medium, polarize toward an invasive and motile phenotype, in agreement with transcriptomic modulations, including the up-regulation of Nanog and Oct4. Overexpression of these genes was shown to be associated with poor prognosis and metastatic forms of some cancers. We thus investigated implication of Nanog and Oct4, two embryonic transcription factors, in melanoma motility., Methods: Our team used stable transfection of Nanog or Oct4 in A375 melanoma cell line to investigate motility in a wound healing assay and a transendothelial migration assay. Using semiquantitative RT-PCR, expression of two gene panels involved either in mesenchymal motility or in amoeboid migration was studied., Results: Strongly enhanced capacities of motility and extravasation were observed with cells overexpressing Oct4 and Nanog. The A375 cell line has been described as having a mesenchymal migration type. However, in the Oct4 and Nanog transfectants, several amoeboid migration markers are strongly induced. Accordingly, amoeboid migration inhibitors decrease significantly the transmigration of Oct4- and Nanog-expressing cells through endothelial cells., Conclusions: We propose here that Nanog and Oct4 pluripotency marker expression in melanoma cells increases the transmigration capacity of these cells through the gain of amoeboid motility, leading to higher invasiveness and aggressiveness.