From preneoplastic lesion to heterogenous tumor: recent insights into hepatoblastoma biology and therapeutic opportunities.

Hepatoblastoma is the most common pediatric liver cancer, with the fastest rising incidence among childhood malignancies. Early genomic studies revealed that hepatoblastoma has the lowest mutational burden of any human cancer, however, recent advances in single-cell RNA-seq, multiomics, spatial transcriptomics, and functional genomics screenings have revealed substantial complexity. Diverse cellular subpopulations, divergent WNT signaling, key developmental pathways, and intricate interactions between the tumor cells and tumor immune microenvironment (TME) collectively shape tumor heterogeneity, disease progression, therapeutic responses, and genetic dependencies. Mosaic embryonic loss of heterozygosity (LOH) at chromosome 11p15.5 may be a hepatoblastoma-initiating event, as clonal expansion of 11p15.5 LOH occurs in adjacent normal liver tissue. A cholangiocyte-like subpopulation expresses FGF19, in a SOX4-dependent, paracrine manner, to drive the proliferation of neighboring embryonal hepatoblastoma cells. WNT-signaling dependent MDK promotes the immunosuppressive TME, which impairs immune cell infiltration. The TME may also be driven by islands of erythroblasts, which influence treatment resistance. Plasticity driven by changes in chromatin accessibility enables differentiation transition between hepatocytic and liver progenitor cell types, which is associated with treatment resistance. Here, we review recent findings in pediatric hepatoblastoma cells, tumor-associated cell types, and genetic dependencies that will serve to advance hepatoblastoma therapy. Clinical trial number: Not applicable.