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A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma

Author

Listed:
  • Tim Groningen

    (Amsterdam UMC University of Amsterdam)

  • Nurdan Akogul

    (Amsterdam UMC University of Amsterdam)

  • Ellen M. Westerhout

    (Amsterdam UMC University of Amsterdam)

  • Alvin Chan

    (Amsterdam UMC University of Amsterdam)

  • Nancy E. Hasselt

    (Amsterdam UMC University of Amsterdam)

  • Danny A. Zwijnenburg

    (Amsterdam UMC University of Amsterdam)

  • Marloes Broekmans

    (Amsterdam UMC University of Amsterdam)

  • Peter Stroeken

    (Amsterdam UMC University of Amsterdam)

  • Franciska Haneveld

    (Amsterdam UMC University of Amsterdam)

  • Gerrit K. J. Hooijer

    (Amsterdam UMC University of Amsterdam)

  • C. Dilara Savci-Heijink

    (Amsterdam UMC University of Amsterdam)

  • Arjan Lakeman

    (Amsterdam UMC University of Amsterdam)

  • Richard Volckmann

    (Amsterdam UMC University of Amsterdam)

  • Peter Sluis

    (Amsterdam UMC University of Amsterdam)

  • Linda J. Valentijn

    (Amsterdam UMC University of Amsterdam)

  • Jan Koster

    (Amsterdam UMC University of Amsterdam)

  • Rogier Versteeg

    (Amsterdam UMC University of Amsterdam)

  • Johan Nes

    (Amsterdam UMC University of Amsterdam)

Abstract

Transition between differentiation states in development occurs swift but the mechanisms leading to epigenetic and transcriptional reprogramming are poorly understood. The pediatric cancer neuroblastoma includes adrenergic (ADRN) and mesenchymal (MES) tumor cell types, which differ in phenotype, super-enhancers (SEs) and core regulatory circuitries. These cell types can spontaneously interconvert, but the mechanism remains largely unknown. Here, we unravel how a NOTCH3 intracellular domain reprogrammed the ADRN transcriptional landscape towards a MES state. A transcriptional feed-forward circuitry of NOTCH-family transcription factors amplifies the NOTCH signaling levels, explaining the swift transition between two semi-stable cellular states. This transition induces genome-wide remodeling of the H3K27ac landscape and a switch from ADRN SEs to MES SEs. Once established, the NOTCH feed-forward loop maintains the induced MES state. In vivo reprogramming of ADRN cells shows that MES and ADRN cells are equally oncogenic. Our results elucidate a swift transdifferentiation between two semi-stable epigenetic cellular states.

Suggested Citation

  • Tim Groningen & Nurdan Akogul & Ellen M. Westerhout & Alvin Chan & Nancy E. Hasselt & Danny A. Zwijnenburg & Marloes Broekmans & Peter Stroeken & Franciska Haneveld & Gerrit K. J. Hooijer & C. Dilara , 2019. "A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09470-w
    DOI: 10.1038/s41467-019-09470-w
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    Cited by:

    1. Bieke Decaesteker & Amber Louwagie & Siebe Loontiens & Fanny De Vloed & Sarah-Lee Bekaert & Juliette Roels & Suzanne Vanhauwaert & Sara De Brouwer & Ellen Sanders & Alla Berezovskaya & Geertrui Deneck, 2023. "SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Cécile Thirant & Agathe Peltier & Simon Durand & Amira Kramdi & Caroline Louis-Brennetot & Cécile Pierre-Eugène & Margot Gautier & Ana Costa & Amandine Grelier & Sakina Zaïdi & Nadège Gruel & Irène Ji, 2023. "Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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