Investigating YAP1 control of differentiation and metabolism in Hepatoblastoma
Jordan L. Smith | Xue Lab | F30 Award
Hepatoblastoma (HB), the most common pediatric primary liver tumor, affects children from infancy to five years of age. Surgical resection with adjuvant chemotherapy has saved many young lives. However, the five-year survival rate remains at 70%, and is worse for children with unresectable tumors. Meeting the clinical need for HB-targeted therapies requires a better understanding of how HB tumors are formed and maintained. The transcriptional co-regulator YAP1 is hyper-activated in 79% of HB cases, and recent studies suggest that YAP1 and the Wnt/β-catenin pathway act together to initiate HB tumors. But is YAP1 required to maintain HB tumorigenesis? Preliminary studies using a conditional mouse model of HB—driven by doxycycline-inducible hyperactive YAP1S127A and constitutively active β-catenin—suggest that YAP1 is essential for tumor maintenance. In the presence of doxycycline, YAP1 is expressed, and mice develop HB tumors; withdrawing doxycycline turns off YAP1, resulting in >90% tumor regression within 10 weeks. Transcriptional analyses revealed that hepatocyte differentiation factors and liver metabolic genes were induced in regressing tumors.
