Development of Liver Cancer Model Systems and Therapeutic Discovery

Although ICC’s are highly aggressive and increasing in incidence, their pathogenesis remains poorly understood. Recent studies have revealed considerable genetic heterogeneity between individual tumors, including mutations in IDH1/2, and have indicated considerable genetic heterogeneity between individual tumors. A key limitation in the field includes a paucity of experimental systems with which to define the contributions of the lesions to biliary cancer progression. We have established a series of genetically engineered mouse models that incorporate combinations of the major mutations found in the human disease. In addition, our ongoing efforts include the development of a human ICC xenograft and primary cell line bank and the use of these systems for genetic and small-molecule screening in genetically defined subtypes of this cancer.

The Hippo pathway is a conserved regulator of organ size. We have shown that this pathway is central for controlling the quiescence of liver progenitor cells, and that its loss leads to massive liver overgrowth and development of both major types of liver cancer (hepatocellular carcinoma and ICC). The lab is studying the key molecular mediators of tumorigenesis controlled by the Hippo pathway, determining the contribution of Hippo deregulation to subtypes of human liver cancer, and establishing approaches to target it therapeutically.