Abstract IA04: Identifying and targeting tumorigenic signals in the developing liver

Abstract

Many childhood cancers originate in embryonic precursors and develop during periods of rapid growth, yet the unique mechanisms of tumorigenesis during development have remained understudied due to the rarity of these cancers and a relative lack of experimental tools. Hepatoblastoma, the most common pediatric liver cancer, serves as an excellent model to address this gap in knowledge due to 1) its characteristic development during infancy and early childhood, 2) its exceedingly low mutational burden, and 3) novel methods we have developed to culture primary patient-derived tumor cells (Wu and Nusse, Methods Mol Biol 2022) and to model somatic mutagenesis during embryonic and postnatal liver development in mice (unpublished). Our goal is to uncover mechanisms that promote hepatoblastoma growth during development, which may broadly apply to other pediatric solid tumors. Through histology-based transcriptomics of primary tumor specimens and functional studies of patient-derived tumoroids, we recently discovered that hepatobiliary lineage programs modulate the transcriptional outcome of CTNNB1 mutations, which are nearly universal in hepatoblastoma and result in constitutive Wnt activation (Wu et al., Nat Commun 2024). Hepatoblastoma cells with biliary differentiation, marked by expression of the transcription factor SOX4, produce a growth factor FGF19 that provides a required proliferative signal for surrounding tumor cells that show hepatocytic differentiation and express the cognate receptor/co-receptor FGFR4/KLB (Wu et al., Nat Commun 2024). Thus, the distinct lineage programs active in hepatoblastoma cells promote paracrine signaling that fuels bulk tumor growth. Work in my lab now focuses on identifying upstream regulators and downstream targets of hepatobiliary transcription factors in hepatoblastoma cells and characterizing the lineage relationships between different tumor cell types. To complement our studies in human patient-derived tumoroids, we are developing new mouse models to identify tumorigenic signals in the developing liver and to probe the consequences of somatic Wnt activation in the liver during embryonic and postnatal development. Finally, we aim to elucidate mechanisms of cisplatin resistance and identify new therapeutic targets in relapsed/refractory pediatric liver cancer. In collaboration with the Perentesis lab at CCHMC, we have used a 3,877-compound drug repurposing library to test cisplatin-resistant patient-derived tumoroids in single-agent and dual-agent screens with low dose cisplatin. In addition to validating previously reported effective agents in pediatric liver cancers, we have identified several novel drug hits with in vitro efficacy as single agents and/or in synergy with cisplatin. Work is ongoing to validate these hits across tumoroids and orthotopic xenograft models and to understand the mechanisms by which these agents can circumvent chemoresistance in pediatric liver cancer.