Single-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma
Amélie Roehrig, Théo Z. Hirsch, Aurore Pire, Guillaume Morcrette, Barkha Gupta, Charles Marcaillou, Sandrine Imbeaud, Christophe Chardot, Emmanuel Gonzalès, Emmanuel Jacquemin, Masahiro Sekiguchi, Junko Takita, Genta Nagae, Eiso Hiyama, Florent Guérin, Monique Fabrè, Isabelle Aerts, Sophie Taque, Véronique Laithier, Sophie Branchereau, Catherine Guettier, Laurence Brugières, Brice Fresneau, Jessica Zucman‐Rossi, Éric Letouzé
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.