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

Amélie Roehrig, Theo Z. Hirsch, Aurore Pire, Guillaume Morcrette, Barkha Gupta, Charles Marcaillou, Sandrine Imbeaud, Christophe Chardot, Emmanuel Gonzales, Emmanuel Jacquemin, Masahiro Sekiguchi, Junko Takita, Genta Nagae, Eiso Hiyama, Florent Guérin, Monique Fabre, Isabelle Aerts, Sophie Taque, Véronique Laithier, Sophie Branchereau, Catherine Guettier, Laurence Brugières, Brice Fresneau, Jessica Zucman-Rossi () and Eric Letouzé ()
Additional contact information
Amélie Roehrig: INSERM
Theo Z. Hirsch: INSERM
Aurore Pire: INSERM
Guillaume Morcrette: INSERM
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
Genta Nagae: the University of Tokyo
Eiso Hiyama: Hiroshima University Hospital
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
Eric Letouzé: INSERM

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47280-x

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