Formation of the Vasculogenic Mimicry Phenotype in Melanoma Mel Z Cells Is Coupled with Changes in Inter-Chromosomal Contacts of Developmental Genes with rDNA Clusters.

Upon transferal from plastic to Matrigel, melanoma cells demonstrate growth in three dimensions and form de novo vascular networks-known as vasculogenic mimicry-that are characteristic of the stemness phenotype of aggressive tumors. It has been reported that during malignant transformation, stress, or differentiation, the long-range inter-chromosomal interactions between numerous developmental genes and nucleoli are changed. The aim of this work was to study the potential mechanisms behind the development of the vasculogenic mimicry phenotype in melanoma cells and whether the formation of these 3D structures is connected with the reorganization of inter-chromosomal contacts of rDNA clusters. Here, we show that after 15 h of growth on Matrigel, and following the formation of the vasculogenic mimicry phenotype, dramatic changes occur in Mel Z cells in rDNA contacts with different genomic regions that possess mainly developmental genes. Approximately 400 genes that retained stable contacts with nucleoli were co-expressed with different lincRNAs and were highly associated with H3K27me3 marks and simultaneously regulated by different transcription factors. These genes are involved in development and cell adhesion and may control the basic stage of differentiation. The genes that acquired or increased contacts with rDNA clusters during growth on Matrigel are associated with cell morphogenesis, cell junctions, and the cytoskeleton. Here, we present the first evidence that nucleoli may be involved in both the activation and repression of particular groups of developmental rDNA-contacting genes in melanoma cells forming the vasculogenic mimicry phenotype. We conclude that the inter-chromosomal interactions between developmental genes and rDNA clusters are dynamic, and that nucleoli play an important role in the development of vasculogenic mimicry and stemness phenotypes in aggressive tumor genes.