New information about the origin of rare liver tumors in children

Liver cancer in children is rare, but when it does occur the two main types are hepatoblastoma (HB) and hepatocellular carcinoma (HCC). However, in some cases, tumors show characteristics of both types. These tumors are classified into a third tumor category called hepatoblastoma with carcinoma features (HBC).

There are many unanswered questions about tumors in this category, but a current study published Hepatology Journal, Researchers at Baylor College of Medicine, Texas Children’s Hospital, and partner institutions have revealed valuable insights into the cellular composition of HBCs and the relationship between different cell types in tumors. The findings have implications for the response of tumors to therapies and the understanding of how HBC tumors emerge.

In 2022, our team identified HBC as the third group of liver tumor types in children. In the present study, we applied multiple genetic profiling techniques to characterize the composition of 42 HBCs, mapping the origin of different cell types and their responses to treatment.

Dr. Pavel Sumazin, co-corresponding author, Professor of Pediatrics, Hematology-Oncology at Baylor

Sumazin is also a member of the Dan L. Duncan Comprehensive Cancer Center and the Department of Quantitative and Computational Biosciences at Baylor.

Using DNA and RNA single-cell sequencing – a technique for studying thousands of tumor cells at a time – researchers found that HBc tumors contained three types of cancer cells: HBc-like cells, HCC-like cells and HBc-specific cells, which show molecular features of both HBs and HCC. “HBCs arise from liver stem cells and this type of undifferentiated tumor cells are less responsive to chemotherapy and immunotherapy,” Sumazin said.

Analyzing treatment outcome data from 41 patients showed that children with HbC tumors had worse survival rates than children with normal HbC. “The 5-year overall survival is about 80% for HB patients and about 40% for HbC patients, but transplanted HbC patients do better,” Sumazin said. “This significant difference underscores the importance of understanding why HBc tumors are so resistant to treatment.”

When the team investigated the relationship between different molecular cell types in HBc tumors, they found that HBc cells arise from HB progenitors and can transition toward HCC, highlighting a molecular continuum between HBs and HCC.

“These transitions (HBs → HBC → HCC) occur during the early embryonic stages of liver development,” Sumazin said. “HBC tumors are composed of cells that have undergone differentiation arrest and retain molecular and other characteristic features of early hepatic stem cells.”

These HB → HBC → HCC transitions occur when the WNT signaling pathway is impaired. “This pathway plays an early role in normal liver development: It is very active in stem cells and then normally becomes quiescent to allow the cells to differentiate,” Sumazin said. “But in all HBc tumors, WNT remains active and prevents cells from growing normally. Inhibiting WNT signaling promotes cell differentiation and increases sensitivity to chemotherapy.”

Studies show that the process leading to HBc tumors is dynamic and involves multiple HBs-to-HBc and HBc-to-HCC transitions. “We showed that HBCs do not arise from a single progenitor cell, but rather arise from multiple HBC cells that independently undergo tumor-type transition into HBCs.”

Together, these findings provide a new developmental model of pediatric liver cancer, linking sustained WNT signaling during early liver development to tumor heterogeneity, tumor-type transitions, and patient outcomes.