Human melanocytes: Control vs. RAS or BRAF Infected
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE50911 | GEO | 2016/01/31
SECONDARY ACCESSION(S): PRJNA219343
REPOSITORIES: GEO
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Project description:Spotted oligonucleotide microarrays were used to assess global differential gene expression comparing normal human melanocytes with six independent melanoma cell strains from advanced lesions. The data, validated at the protein level for selected genes, confirmed the overexpression in melanoma cells relative to normal melanocytes of several genes in the growth factor/receptor family that confer growth advantage and metastasis. In addition, novel pathways and patterns of associated expression in melanoma cells not reported before emerged. Six melanoma cultures and two melanocyte cultures. The melanoma cultures are considered, for the purposes of this investigation, replicates from the point of view that they are all melanomas. Three of the melanomas were replicated once or twice in addition.
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Project description:We compared the transformation efficiencies of mutant NRAS and KRAS in immortal, non-transformed Ink4a/Arf-deficient melanocytes. NRAS mutation leads to increased cellular proliferation and is potently tumorigenic. In contrast, KRAS mutation does not enhance melanocyte proliferation and is only weakly tumorigenic on its own. While both NRAS and KRAS activate MAPK signaling, only NRAS enhances MYC activity in these cells. Our data suggests that the activity of specific RAS isoforms is context dependent and provides a possible explanation for the prevalence of NRAS mutations in melanoma.In addition, understanding this mechanism will have important implications for cancer therapies targeting RAS pathways. Keywords: RAS isoforms Common Reference
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Project description:Ultraviolet (UV) radiation is a major melanoma risk factor, yet underlying mechanisms remain poorly understood. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon-response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-gamma (IFN-gamma), but not type-I interferons. IFN-gamma was produced by macrophages recruited to neonatal skin by UVB-induced chemokine receptor Ccr2 ligands. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-gamma blockade abolished macrophage-associated melanoma growth and survival. IFN-gamma-producing macrophages were identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-gamma in promoting melanocytic cell survival/immunoevasion, and suggest IFN-gamma-R signaling represents a novel therapeutic melanoma target.
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Project description:Little is known about the mechanisms underlying the localization of human melanocytes during embryogenesis, and how the characteristics of melanocytes differ in various body sites. Immunohistochemical studies of biopsy tissue obtained from four different anatomic sites (scalp, back, abdomen, and sole) of 31 aborted fetuses following the approval of the ethics committee for the study of human gene analysis revealed that the melanocyte-associated marker gp100 was expressed earlier in embryogenesis than other melanocyte markers. Human fetal melanocytes are initially localized in the epidermis, and then migrate to the hair buds from the epidermis but not the dermis. In the sole, melanocytes localize in eccrine sweat gland ducts. Cultured fetal melanocytes did not stain positively for any melanocyte markers other than MITF and nestin. When co-cultured with normal human keratinocytes and fibroblasts, fetal melanocytes stained positively for gp100. Gene expression studies indicated that fetal melanocytes were topographically diverse, especially sole-derived melanocytes compared with other melanocytes. Expression of several genes, including CHI3L1 and FGF7, was higher in sole-derived melanocytes. These findings suggest that human fetal melanocytes derived from the sole have different profiles both in vivo and in vitro compared with melanocytes from other sites. In this study, microarray analyses were performed using cultured fetal melanocytes from 4 different sites (scalp, back, abdomen and sole) obtained at 19 WOG, and newborn normal epidermal melanocyte as a control. RNA purification was performed using an RNeasy Mini kit (Qiagen, Germany) and those 5 samples, were analyzed using GeneChip 1.0 ST Array (Affymetrix, CA, USA).
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Project description:Somatic oncogenic mutation of BRAF coupled with inactivation of PTEN constitute a frequent combination of genomic alterations driving development of human melanoma. Mice genetically engineered to conditionally express oncogenic BrafV600E and inactivate Pten in melanocytes following tamoxifen treatment rapidly develop melanoma. While early stage melanomas comprised melanin-pigmented Mitf and Dct-expressing cells, expression of these and other melanocyte identity genes was lost in later stage tumours that showed histological and molecular characteristics of de-differentiated neural crest type cells. Melanocyte identity genes displayed loss of active chromatin marks and RNA polymerase II and gain of heterochromatin marks indicating epigenetic reprogramming during tumour progression. Nevertheless, late stage tumour cells grown in culture re-expressed Mitf and melanocyte markers and Mitf together with Sox10 co-regulated a large number of genes essential for their growth. In this melanoma model, somatic inactivation that the catalytic Brg1 (Smarca4) subunit of the SWI/SNF complex and the scaffolding Bptf subunit of the NuRF delayed tumour formation and deregulated large and overlapping gene expression programs essential for normal tumour cell growth. Moreover, we show that Brg1 and Bptf co-regulated many genes together with Mitf and Sox10. Together these transcription factors and chromatin remodelling complexes orchestrate essential gene expression programs in mouse melanoma cells
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