Asynchronous Transitions from Hepatoblastoma to Carcinoma in High-Risk Pediatric Tumors

Most malignant hepatocellular tumors in children are classified as either hepatoblastoma (HB) or hepatocellular carcinoma (HCC), but some tumors demonstrate features of both HB and HCC^1-3. These tumors have been recognized under a provisional diagnostic category by the World Health Organization and are distinguished from HB and HCC by a combination of histological, immunohistochemical, and molecular features^4-6. Their outcomes and cellular composition remain an open question^7-9. The heterogeneous histological and molecular profiles of hepatoblastomas with carcinoma features (HBCs)⁴ may result from cells with combined HB and HCC characteristics (HBC cells) or from mixtures of cells displaying either HB or HCC signatures. We used multiomics profiling to show that HBCs are mixtures of HB, HBC, and HCC cell types. HBC cells are more chemoresistant than HB cells, and their chemoresistance-a driver of poor outcomes^10-12-is determined by their cell types, genetic alterations, and embryonic differentiation stages. We showed that the prognosis of HBCs is significantly worse than that of HBs. We also showed that HBC cells are derived from HB cells at early hepatoblast differentiation stages, that aberrant activation of WNT-signaling initiates HBC transformation, and that WNT inhibition promotes differentiation and increases sensitivity to chemotherapy. Furthermore, our analysis revealed that each HBC is the product of multiple HB-to-HBC and HBC-to-HCC transitions. Thus, multiomics profiling of HBCs provided key insights into their biology and resolved major questions regarding the etiology of these childhood liver tumors.