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Emergence of neural crest identity is a key early step in melanoma formation [ChIP-Seq]

ABSTRACT: The “cancerized field” concept posits that cells of a given tissue share a potentially oncogenic mutation or insult and are thus cancer-prone, yet only discreet clones within the field initiate tumor formation. In melanoma, tumors frequently (~50%) carry the oncogenic BRAFV600E mutation that is also nearly always present in benign nevi that rarely become melanoma. The zebrafish crestin gene is expressed embryonically in neural crest progenitors and is then specifically re-expressed in melanoma tumors. Here, we show by live imaging transgenic zebrafish crestin reporters that single melanocytes in a cancerized field with oncogenic BRAFV600E and p53 tumor suppressor loss undergo a change that recapitulates the neural crest progenitor (NCP) state, and patches of these cells initiate early melanoma. The crestin element is regulated by the NCP transcription factor sox10. Forced sox10 overexpression in melanocytes accelerated melanoma formation, consistent with reprogramming to the NCP state and activation of super-enhancers that lead to melanoma. Our work highlights the importance of the reemergence of the NCP state as a barrier to melanoma initiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE61825 | GEO | 2016/06/08

SECONDARY ACCESSION(S): PRJNA262500

REPOSITORIES: GEO

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Project description:It is believed that the inherent differentiation program of melanocytes during embryogenesis predisposes melanoma cells to high frequency of metastasis. Sox10, a transcription factor expressed in neural crest stem cells and a subset of progeny lineages, plays a key role in the development of melanocytes. We show that B16F10 melanoma cells transfected with siRNA specific for Sox10 display reduced migratory activity which in turn indicated that a subset of transcriptional regulatory target genes of Sox10 are likely to be involved in migration and metastasis of melanoma cells. We carried out microarray-based gene expression profiling using Sox10-specific siRNA to identify regulatory targets and found that multiple genes including melanocortin-1 receptor (Mc1R) partake in the regulation of migration. We provide evidences that a significant portion of the effect of Sox10 on migration is mediated by Mitf, a transcription factor downstream to Sox10. The involvement of Mc1R in migration was studied in detail in vivo using a murine metastasis model. Specifically, B16F10 melanoma cells treated with a specific siRNA showed reduced tendency in metastasizing to and colonizing the lung after being injected in the tail vein. These data reveal a cadre of novel regulators and mediators involved in migration and metastasis of melanoma cells that represent potential targets of therapeutic intervention. Chemically synthesized siRNA duplex (WT1-Sox10) was used to knock-down the transcription factor Sox10 in murine melanoma cell line B16F10. For the control, siRNA containing 5 nucleotide alterations (MT1-Sox10) were used. Total RNA was subsequently prepared to synthesize probes for microarray screening. A total of three pairs of replicate samples were generated each from separate transfection followed by RNA preparation. Expression values were determined and compared within each pair of WT1-Sox10 and MT1-Sox10 transfections. Genes showing over 2 fold changes in all three replicate pairs were subjected to subsequent analyses.

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Emergence of neural crest identity is a key early step in melanoma formation [ChIP-Seq]

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