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Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60666 | GEO | 2015/03/05

SECONDARY ACCESSION(S): PRJNA259210

REPOSITORIES: GEO

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Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state.

Project description:Transcriptional reprogramming of proliferative melanoma cells into a phenotypically distinct invasive cell subpopulation is a critical event at the origin of metastatic spreading. Here we generate transcriptome, open chromatin and histone modification maps of melanoma cultures; and integrate this data with existing transcriptome and DNA methylation profiles from tumour biopsies to gain insight into the mechanisms underlying this key reprogramming event. This shows thousands of genomic regulatory regions underlying the proliferative and invasive states, identifying SOX10/MITF and AP-1/TEAD as regulators, respectively. Knockdown of TEADs shows a previously unrecognized role in the invasive gene network and establishes a causative link between these transcription factors, cell invasion and sensitivity to MAPK inhibitors. Using regulatory landscapes and in silico analysis, we show that transcriptional reprogramming underlies the distinct cellular states present in melanoma. Furthermore, it reveals an essential role for the TEADs, linking it to clinically relevant mechanisms such as invasion and resistance.

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Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state.

Project description:Understanding the molecular processes underlying intra-tumor heterogeneity is of critical importance to improve the efficiency of therapy and overcome drug resistance. In malignant melanoma, heterogeneity is though to arise -at least partly- through epigenetic rather than genetic reprogramming of proliferating cells, leading to the appearance within the primary tumors of a phenotypically distinct invasive cell subpopulation. The invasive melanoma cells are at the origin of metastatic spread and are thought to provide a reservoir of therapeutically resistant cells. To decipher the gene regulatory networks that underlie the proliferative and invasive cellular states we integrated publicly available gene expression and DNA methylation data from tumor biopsies with a newly generated compendium of open chromatin and histone modification profiling of melanoma cultures that are dominant in either of the two subpopulations. Extensive in silico analyses identified SOX10 and MITF, and AP-1 and TEADs as key upstream regulators of the proliferative and invasive transcriptomes, respectively. Knock-down experiments confirmed the implication of TEADs in the invasive gene network and, more importantly, established a causative link between activation of these transcription factors and melanoma cell invasion and sensitivity to MAPK inhibitors.

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