New research indicates that abnormal Wnt signalling is a key driver in the development of a rare and aggressive form of childhood liver cancer. The study focused on hepatoblastomas with carcinoma (HBC) features, a tumor type that combines characteristics of hepatoblastomas (HBs) and hepatocellular carcinomas (HCCs). While HBs generally respond well to chemotherapy, HCCs are more aggressive.
Researchers analyzed 42 HBC tumors using multi-omics profiling, integrating genomic and gene expression data. Their findings suggest HBC cells originate from HB precursor cells arrested at an early liver stem cell stage. This developmental halt is linked to persistent abnormal Wnt signalling, a pathway crucial for cell growth during embryonic development.
Experimental inhibition of Wnt signalling led to increased tumor cell maturation and heightened sensitivity to chemotherapy. This is significant, as undifferentiated liver cells are typically more resistant to treatment, and cisplatin is a standard therapy for pediatric liver cancer.
The study also developed a classifier to identify HBC cells in biphasic tumors. HBC cells constituted approximately 51% of malignant cells, exhibiting identities ranging from HB-like to HCC-like, and some unique molecular profiles.
Clinically, HBCs present a poorer prognosis, with average five-year survival rates of 43% compared to 79% for HBs. HBC cells also demonstrated greater chemoresistance, likely due to their immature, stem-like state.
Despite limitations such as sample size and the prevalence of post-chemotherapy samples, the research provides a clearer understanding of tumor evolution. The precise molecular triggers for the transition to carcinoma-like states remain unknown, with Wnt signalling likely not the sole factor.
Future work aims to use precise molecular definitions to identify high-risk patients earlier and tailor treatments. This could lead to trials investigating Wnt pathway inhibitors alongside chemotherapy, potentially improving survival rates for this challenging pediatric cancer.