Hepatoblastoma Cell Lines: Past, Present and Future

Hepatoblastoma (HB), the most common pediatric liver malignancy, is associated with high cure rates although patients with advanced or recurrent disease have less favorable outcomes. Because patients are invariably <4 years of age, chemotherapies can cause significant long-term morbidities. Immortalized HB cell lines could be of great utility for drug screening, for the identification of novel therapeutic susceptibilities, and for studies requiring highly regulated and/or rapidly changing in vitro environments. However, HB research is hampered by a paucity of established cell lines that could be used for such purposes, with only two human cell lines being readily available and neither of which is representative of the most common HB molecular subtypes. Recently, immortalized cell lines have been derived from murine HBs that are driven by several of the most common oncogenes associated with human tumors. These comprise five distinct groups associated with the deregulation of each of the possible combinations of oncogenic forms of the bcatenin, YAP and NRF2 transcription factors or the over-expression of MYC. All five groups share many of the attributes and molecular signatures of actual human HBs. In addition, they have been used for purposes as diverse as identifying novel molecular targets through the use of CRISPR-based screens and the demonstration that some HB cells can trans-differentiate into endothelial cells that support more robust tumor growth. The experience gained from these models and advances in the propagation of human hepatocytes in mice suggests that it will soon be possible to generate bespoke human HBs and immortalized cell lines.