β-Catenin mutations as determinants of hepatoblastoma phenotypes in mice

Abstract

Hepatoblastoma (HB) is the most common pediatric liver cancer. Although long-term survival of HB is generally favorable, it depends on clinical stage, tumor histology, and a variety of biochemical and molecular features. HB appears almost exclusively before the age of 3 years, is represented by seven histological subtypes, and is usually associated with highly heterogeneous somatic mutations in the catenin β1 (CTNNB1) gene, which encodes β-catenin, a Wnt ligand–responsive transcriptional co-factor. Numerous recurring β-catenin mutations, not previously documented in HB, have also been identified in various other pediatric and adult cancer types. Little is known about the underlying factors that determine the above HB features and behaviors or whether non-HB–associated β-catenin mutations are tumorigenic when expressed in hepatocytes. Here, we investigated the oncogenic properties of 14 different HB– and non-HB–associated β-catenin mutants encoded by Sleeping Beauty vectors following their delivery into the mouse liver by hydrodynamic tail-vein injection. We show that all β-catenin mutations, as well as WT β-catenin, are tumorigenic when co-expressed with a mutant form of yes-associated protein (YAP). However, tumor growth rates, histologies, nuclear-to-cytoplasmic partitioning, and metabolic and transcriptional landscapes were strongly influenced by the identities of the β-catenin mutations. These findings provide a context for understanding at the molecular level the notable biological diversity of HB.

Acquired deficiency of the peroxisomal enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase is a metabolic vulnerability in hepatoblastoma

“…After allowing four weeks for tumor initiation, the animals were divided into four dietary cohorts: 1. standard diet, 2. standard diet+10% (w/w) C12 in the form of glycerol trilaurate (C12 diet), 3. standard diet+10% (w/w) DDDA (DDDA diet) and, 4. standard diet+C12 and DDDA (10% w/w each) (C12+DDDA diet). As previously reported, median survival in the former group was 14.2 wk (19)(20)(21)(22)27) (Fig. 1A).…”

“…We previously observed that murine models of pediatric and adult liver cancer, namely hepatoblastoma (HB) and hepatocellular carcinoma (HCC), as well as their human counterparts, also remodel their metabolism and become more reliant on glycolysis than on fatty acid oxidation (FAO). Consistent with this, total mitochondrial mass and transcripts encoding virtually all enzymes in the mitochondrial-based β-FAO pathway are markedly down-regulated (18)(19)(20)(21)(22).…”

“…They also succumbed by week 12-13 with 10-14 gram tumors ( Fig. 1B) (19,20,22). In contrast, tumors from mice maintained on DDDA diets showed areas of extensive necrosis that was confirmed by histologic examination of H&E-stained tumor sections ( Fig.…”

“…HBs were generated by hydrodynamic tail vein injection (HDTVI) of Sleeping Beauty (SB) vectors encoding a 90 bp in-frame oncogenic deletion mutant of β-catenin [hereafter Δ(90)] and a missense mutant (S127A) of yes-associated protein (hereafter YAP S127A ), the terminal effector of the Hippo signaling pathway (19)(20)(21)(22)27). We refer to these HBs hereafter as Δ(90) tumors.…”

Animal Modeling of Pediatric Liver Cancer

“…HB tumors originating in myc, chrebp, or myc/chrebp knock-out livers grew more slowly, and clear differences in metabolic and gene expression profiling were shown depending on the genetic backgrounds [53]. In 2019, two different publications explored the tumorigenic capacity of different mutant forms of CTNNB1 in combination with constitutively active Yap-1 with this model [54,55]. In a thorough study of the tumorigenic capacity of 14 different mutant forms of CTNNB1 with Yap-1, Zhang and colleagues showed that specific mutant forms of CTNNB1 determine HB tumor growth rates, survival, histologic features, metabolic features, and transcriptional profiles [55].…”