ABNORMAL Wnt signalling appears to drive the development of a rare and high-risk form of childhood liver cancer, according to new research.
The study focused on hepatoblastomas with carcinoma (HBCs) features, an uncommon tumour type that shares characteristics of hepatoblastomas (HBs) and hepatocellular carcinomas (HCCs), the two main primary liver cancers in children. While HBs often respond well to chemotherapy, HCCs typically behave more aggressively. HBCs sit between the two, and it has remained unclear whether they represent true hybrid cancer cells or simply a mixture of distinct HB and HC cell populations.
Wnt Signalling and Tumour Development
Using multi-omics profiling to integrate genomic and gene expression data, researchers analysed the biology, cellular composition and evolutionary patterns of 42 HBC tumours.
Their findings suggest that HBC cells originate from HB precursor cells that become arrested at an early liver stem cell stage. This developmental halt appears to be driven by persistent abnormal Wnt signalling – a pathway that plays a central role in regulating cell growth and differentiation during embryonic development.
When Wnt signalling was inhibited in experimental models, tumour cells showed increased maturation and greater sensitivity to chemotherapy. This is clinically relevant because undifferentiated liver cells are typically more resistant to treatment, and cisplatin remains a cornerstone of paediatric liver cancer therapy.
The team also created a gene expression-based classifier capable of identifying HBC cells even in biphasic tumours, where distinct HBB and HCC regions are expected. Overall, HBC cells accounted for around 51% of malignant cells within these tumours and displayed a spectrum of identities — some resembling HB, others HCC, and some molecularly distinct from both.
Implications For Prognosis and Future Treatment
Clinically, the findings underline the seriousness of HBCs. The researchers reported average five-year survival rates of 43% for HBC, compared with 79% for HB, highlighting the poorer prognosis associated with these tumours. HBC cells also appeared more chemoresistant, likely linked to their immature, stem-like state.
Although the study was limited by its relatively small sample size and the predominance of post-chemotherapy samples, it provides a clearer framework for understanding how these tumours evolve. The authors note that the exact molecular triggers behind the transition from HB to carcinoma-like states remain unknown, and Wnt signalling is unlikely to be the only pathway involved.
Looking ahead, a more precise molecular definition of HBC could help clinicians identify high-risk patients earlier and tailor treatment intensity accordingly. It may also pave the way for trials investigating Wnt pathway inhibitors alongside standard chemotherapy. In the longer term, improved biological classification could allow more accurate tracking of HBC incidence — which is currently uncertain — and support the development of risk-adapted therapies aimed at improving survival in this challenging paediatric cancer.
Reference:
Xinjian Yu et al. Asynchronous transitions from high-risk hepatoblastoma to carcinoma. J. Hepatol. 2026; doi:10.1016/j.jhep.2026.02.023
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