title: Plasticity of melanoma cells induced by neural cell crest conditions and three-dimensional growth.
abstract: Melanoma tumors have been shown to comprise both invasive and proliferative cell subpopulations. These populations are highly plastic, thus hampering full characterization and therapeutic targeting of dormant and partially dedifferentiated invasive cells. We have reported, previously, that melanoma cells grown in a serum-free neural crest medium, in which they propagate as spheroids, show higher invasiveness and increased immune escape. In addition, in spheroids, we showed the increased expression of several genes which are involved in pluripotency, differentiation, and invasion. We therefore proposed that these culture conditions favor the polarization of proliferative melanoma cells toward an invasive state. As plasticity may suggest a reversible polarization, the aim of this report is to assess the transient phenotype of invasive cells generated through this procedure. We provide evidence that spheroid cells mimic dormant populations, and that this phenotype is fully reversible when cells are reintroduced into culture media that contain serum in which they grow as a monolayer. We also show that most transcriptional deregulations can be reversed. To further explain this plasticity in melanoma cells, we explored the epigenetic status of four gene promoters, assuming changes in acetylation or dimethylation on histone 3. We show reversible modifications on lysine 9 and lysine 4. We propose that spheroids allow the transient polarization of melanoma cells toward enhanced dormancy, loss of differentiation, and invasiveness, thereby reproducing the properties and plasticity of invasive subpopulations in melanoma tumors. This in-vitro model will allow further characterization and targeting of melanoma invasive cell populations.
authors.affiliation: Centre National de la Recherche Scientifique, UMR 7592, Jacques Monod Institute, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ghislin
authors.forename: Frederique
authors.initials: F
authors.lastname: Deshayes
authors.forename: Jessica
authors.initials: J
authors.lastname: Lauriol
authors.forename: Sandrine
authors.initials: S
authors.lastname: Middendorp
authors.forename: Isabelle
authors.initials: I
authors.lastname: Martins
authors.forename: Reem
authors.initials: R
authors.lastname: Al-Daccak
authors.forename: Catherine
authors.initials: C
authors.lastname: Alcaide-Loridan
mesh_terms: D000107:Acetylation; D002448:Cell Adhesion; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly; D016895:Culture Media, Serum-Free / Q000737:chemistry / Q000378:metabolism; D003640:Dealkylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009432:Neural Crest / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D018874:Spheroids, Cellular; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D059016:Tumor Microenvironment
chemical_list: D016895:Culture Media, Serum-Free; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D008239:Lysine