Abstract 1574: The Hippo pathway regulates liver development and tumorigenesis in zebrafish.

Abstract The Hippo pathway is a novel signaling cascade that regulates cell proliferation, organ size and tumorigenesis in mammals. In mice, deregulation of the Hippo pathway in the liver has been shown to potently induce tumor formation. However, the molecular mechanism by which the Hippo pathway regulates hepatic growth is not well understood. In this study, we have examined liver development in NF2-/- mutant zebrafish, which exhibit systemic activation of Yap, and found that liver size was increased by 5 days post fertilization (dpf). Histological evaluation of the NF2-/- mutant zebrafish embryos revealed that the enlarged liver was composed of an extended biliary network. In order to examine the cell-autonomous effects of Yap activation in hepatocytes, we generated Tg(fabp10a:YapS87A) fish and found that liver size increased dramatically by 5 dpf. In contrast to the NF2-/- mutant, histological and FACS analysis revealed that the enlarged liver in the Tg(fabp10a:YapS87A) embryos was composed of a greater number of hepatocytes. Chemical exposure to the γ-secretase inhibitor DAPT or erlotinib rescued the hepatomegaly phenotype in 5 dpf Tg(fabp10a:YapS87A) embryos, indicating dependence on Notch and EGFR signaling pathways. To gain greater insight into how these developmental studies relate to tumorigenesis, we compared NF2+/- mutants and Tg(fabp10a:YapS87A) adults and found that both lines were predisposed to liver tumor formation, developing predominantly intrahepatic cholangiocarcinomas. Together, these studies reveal an evolutionarily conserved role of the Hippo pathway at the interface between liver development and tumorigenesis in zebrafish. Citation Format: Andrew G. Cox, Sebastian Beltz, Kimberley Evason, Didier Y. Stainier, Trista E. North, Wolfram Goessling. The Hippo pathway regulates liver development and tumorigenesis in zebrafish. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1574. doi:10.1158/1538-7445.AM2013-1574