Single-cell Multiomics Reveals the Interplay of Clonal Evolution and Cellular Plasticity in Hepatoblastoma

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Apr 8

PMID 38589411

Authors

Amelie 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 Guerin

Monique Fabre

Isabelle Aerts

Sophie Taque

Veronique Laithier

Sophie Branchereau

Catherine Guettier

Laurence Brugieres

Brice Fresneau

Jessica Zucman-Rossi

Eric Letouze

Affiliations

Soon will be listed here.

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.

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