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Single-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma

Author

Listed:
  • Amélie Roehrig

    (INSERM)

  • Theo Z. Hirsch

    (INSERM)

  • Aurore Pire

    (INSERM)

  • Guillaume Morcrette

    (INSERM
    APHP)

  • Barkha Gupta

    (INSERM)

  • Charles Marcaillou

    (IntegraGen SA)

  • Sandrine Imbeaud

    (INSERM)

  • Christophe Chardot

    (Necker Hospital)

  • Emmanuel Gonzales

    (University of Paris-Saclay)

  • Emmanuel Jacquemin

    (University of Paris-Saclay)

  • Masahiro Sekiguchi

    (The University of Tokyo)

  • Junko Takita

    (The University of Tokyo
    Kyoto University)

  • Genta Nagae

    (the University of Tokyo)

  • Eiso Hiyama

    (Hiroshima University Hospital
    Hiroshima University)

  • Florent Guérin

    (Paris-Saclay University)

  • Monique Fabre

    (AP-HP)

  • Isabelle Aerts

    (PSL Research University)

  • Sophie Taque

    (CHU Fontenoy)

  • Véronique Laithier

    (Centre Hospitalier Universitaire Besançon)

  • Sophie Branchereau

    (Paris-Saclay University)

  • Catherine Guettier

    (Paris-Saclay University)

  • Laurence Brugières

    (Department of Children and Adolescents Oncology)

  • Brice Fresneau

    (Department of Children and Adolescents Oncology)

  • Jessica Zucman-Rossi

    (INSERM
    Assistance Publique Hôpitaux de Paris)

  • Eric Letouzé

    (INSERM
    CNRS
    University Hospital Hôtel-Dieu)

Abstract

Hepatoblastomas (HB) display heterogeneous cellular phenotypes that influence the clinical outcome, but the underlying mechanisms are poorly understood. Here, we use a single-cell multiomic strategy to unravel the molecular determinants of this plasticity. We identify a continuum of HB cell states between hepatocytic (scH), liver progenitor (scLP) and mesenchymal (scM) differentiation poles, with an intermediate scH/LP population bordering scLP and scH areas in spatial transcriptomics. Chromatin accessibility landscapes reveal the gene regulatory networks of each differentiation pole, and the sequence of transcription factor activations underlying cell state transitions. Single-cell mapping of somatic alterations reveals the clonal architecture of each tumor, showing that each genetic subclone displays its own range of cellular plasticity across differentiation states. The most scLP subclones, overexpressing stem cell and DNA repair genes, proliferate faster after neo-adjuvant chemotherapy. These results highlight how the interplay of clonal evolution and epigenetic plasticity shapes the potential of HB subclones to respond to chemotherapy.

Suggested Citation

  • Amélie Roehrig & Theo Z. Hirsch & Aurore Pire & Guillaume Morcrette & Barkha Gupta & Charles Marcaillou & Sandrine Imbeaud & Christophe Chardot & Emmanuel Gonzales & Emmanuel Jacquemin & Masahiro Seki, 2024. "Single-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47280-x
    DOI: 10.1038/s41467-024-47280-x
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    References listed on IDEAS

    as
    1. Katharina T. Schmid & Barbara Höllbacher & Cristiana Cruceanu & Anika Böttcher & Heiko Lickert & Elisabeth B. Binder & Fabian J. Theis & Matthias Heinig, 2021. "scPower accelerates and optimizes the design of multi-sample single cell transcriptomic studies," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    2. Genta Nagae & Shogo Yamamoto & Masashi Fujita & Takanori Fujita & Aya Nonaka & Takayoshi Umeda & Shiro Fukuda & Kenji Tatsuno & Kazuhiro Maejima & Akimasa Hayashi & Sho Kurihara & Masato Kojima & Tomo, 2021. "Genetic and epigenetic basis of hepatoblastoma diversity," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Michael Lawrence & Wolfgang Huber & Hervé Pagès & Patrick Aboyoun & Marc Carlson & Robert Gentleman & Martin T Morgan & Vincent J Carey, 2013. "Software for Computing and Annotating Genomic Ranges," PLOS Computational Biology, Public Library of Science, vol. 9(8), pages 1-10, August.
    4. Hanbing Song & Simon Bucher & Katherine Rosenberg & Margaret Tsui & Deviana Burhan & Daniel Hoffman & Soo-Jin Cho & Arun Rangaswami & Marcus Breese & Stanley Leung & María V. Pons Ventura & E. Alejand, 2022. "Single-cell analysis of hepatoblastoma identifies tumor signatures that predict chemotherapy susceptibility using patient-specific tumor spheroids," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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