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

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  • Annelien Verfaillie

    (Laboratory of Computational Biology, Center for Human Genetics, University of Leuven)

  • Hana Imrichova

    (Laboratory of Computational Biology, Center for Human Genetics, University of Leuven)

  • Zeynep Kalender Atak

    (Laboratory of Computational Biology, Center for Human Genetics, University of Leuven)

  • Michael Dewaele

    (Laboratory for Molecular Cancer Biology, Center for Human Genetics, University of Leuven
    VIB Center for the Biology of Disease)

  • Florian Rambow

    (Laboratory for Molecular Cancer Biology, Center for Human Genetics, University of Leuven
    VIB Center for the Biology of Disease)

  • Gert Hulselmans

    (Laboratory of Computational Biology, Center for Human Genetics, University of Leuven)

  • Valerie Christiaens

    (Laboratory of Computational Biology, Center for Human Genetics, University of Leuven)

  • Dmitry Svetlichnyy

    (Laboratory of Computational Biology, Center for Human Genetics, University of Leuven)

  • Flavie Luciani

    (Laboratory for Molecular Cancer Biology, Center for Human Genetics, University of Leuven
    VIB Center for the Biology of Disease)

  • Laura Van den Mooter

    (VIB Center for the Biology of Disease
    Laboratory of Growth Control and Cancer Research, Center for Human Genetics, University of Leuven)

  • Sofie Claerhout

    (VIB Center for the Biology of Disease
    Laboratory of Growth Control and Cancer Research, Center for Human Genetics, University of Leuven)

  • Mark Fiers

    (VIB Center for the Biology of Disease)

  • Fabrice Journe

    (Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles)

  • Ghanem-Elias Ghanem

    (Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles)

  • Carl Herrmann

    (DKFZ Heidelberg)

  • Georg Halder

    (VIB Center for the Biology of Disease
    Laboratory of Growth Control and Cancer Research, Center for Human Genetics, University of Leuven)

  • Jean-Christophe Marine

    (Laboratory for Molecular Cancer Biology, Center for Human Genetics, University of Leuven
    VIB Center for the Biology of Disease)

  • Stein Aerts

    (Laboratory of Computational Biology, Center for Human Genetics, University of Leuven)

Abstract

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.

Suggested Citation

  • Annelien Verfaillie & Hana Imrichova & Zeynep Kalender Atak & Michael Dewaele & Florian Rambow & Gert Hulselmans & Valerie Christiaens & Dmitry Svetlichnyy & Flavie Luciani & Laura Van den Mooter & So, 2015. "Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state," Nature Communications, Nature, vol. 6(1), pages 1-16, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7683
    DOI: 10.1038/ncomms7683
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    Cited by:

    1. Guillaume Harmange & Raúl A. Reyes Hueros & Dylan L. Schaff & Benjamin Emert & Michael Saint-Antoine & Laura C. Kim & Zijian Niu & Shivani Nellore & Mitchell E. Fane & Gretchen M. Alicea & Ashani T. W, 2023. "Disrupting cellular memory to overcome drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Dianne Lumaquin-Yin & Emily Montal & Eleanor Johns & Arianna Baggiolini & Ting-Hsiang Huang & Yilun Ma & Charlotte LaPlante & Shruthy Suresh & Lorenz Studer & Richard M. White, 2023. "Lipid droplets are a metabolic vulnerability in melanoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Claudia Capparelli & Timothy J. Purwin & McKenna Glasheen & Signe Caksa & Manoela Tiago & Nicole Wilski & Danielle Pomante & Sheera Rosenbaum & Mai Q. Nguyen & Weijia Cai & Janusz Franco-Barraza & Ric, 2022. "Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Miles C. Andrews & Junna Oba & Chang-Jiun Wu & Haifeng Zhu & Tatiana Karpinets & Caitlin A. Creasy & Marie-Andrée Forget & Xiaoxing Yu & Xingzhi Song & Xizeng Mao & A. Gordon Robertson & Gabriele Roma, 2022. "Multi-modal molecular programs regulate melanoma cell state," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    5. Marc A. Vittoria & Nathan Kingston & Kristyna Kotynkova & Eric Xia & Rui Hong & Lee Huang & Shayna McDonald & Andrew Tilston-Lunel & Revati Darp & Joshua D. Campbell & Deborah Lang & Xiaowei Xu & Crai, 2022. "Inactivation of the Hippo tumor suppressor pathway promotes melanoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Michael F. Emmons & Richard L. Bennett & Alberto Riva & Kanchan Gupta & Larissa Anastasio Da Costa Carvalho & Chao Zhang & Robert Macaulay & Daphne Dupéré-Richér & Bin Fang & Edward Seto & John M. Koo, 2023. "HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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