Developmental signaling pathways govern the formation and function of stem cells, thereby holding the key to unlocking the promise of adult tissue regeneration, and inhibiting cancer development. In our laboratory, we use zebrafish as the primary model to study organogenesis, regeneration and carcinogenesis. Our work focuses on the liver, where we explore the regulation of endodermal progenitor cell specification, organ differentiation and growth. We also examine the role of these pathways in zebrafish models of liver regeneration following both surgical and chemical injury, as well as in carcinogenesis. We are using mouse models to demonstrate evolutionary conservation and relevance for human biology.
Recently, we have shown that the wnt signaling pathway is an important regulator of liver development and liver regeneration. We found that prostaglandin positively interacts with and is required for wnt activity to exert its effect in these processes, offering a chance to therapeutically modify wnt-mediated stem and progenitor cell growth. In an effort to identify new regulatory pathways and genes important for liver development, we have initiated a genetic screen; to date we have identified several mutants with disturbed liver formation. In addition, we are proceeding with a chemical genetic screen, using a library of known biologics, to characterize signaling pathways relevant to liver growth. Among the initial set of compounds identified, one pathway has shown potential for regulating hepatic regeneration after injury and cancer progression. Prior work has shown us that we can translate our findings in the zebrafish to the bedside; we are currently planning the first clinical trial that originated from findings in the fish.