Grant: CIHR Fellowship

There are over 100 known liver diseases caused by a variety of factors that affect people of all ages. Among them, liver cancer is the 5th most common cancer and the leading cause of cancer deaths worldwide. The lethality of this disease is due primarily to the late diagnosis and few therapeutic options. An intracellular signaling pathway, Hippo signaling pathway, regulates many cellular functions including cell growth, death, motility and differentiation. Animal studies have demonstrated that Hippo signaling pathway is critical in regulating liver size, liver cell fate and is a potential tumor suppressor for liver. While recent studies have characterized the core components of this pathway, its upstream regulators remain poorly defined. Cell-cell contact is mediated, in part, through the interaction of proteins, called cadherin, that are present on the outside of the cell. Loss of cell-cell contact is associated with the progression and poor prognosis of liver cancer. Interestingly, the Hippo signaling pathway is required for cell-cell contact-induced inhibition of cell proliferation. However, it is not yet known whether loss of cell-cell contact regulates Hippo signaling pathway in liver cells. In this proposal, I will use mouse and cell culture models to explore the upstream regulators of the Hippo signaling pathway in liver cells. I am are particularly interested in how loss of cadherin molecules can regulate Hippo signaling pathway and subsequently contribute to the liver development and cancer progression. The findings generated from this proposal will increase our understanding of the underlying molecular mechanisms that involved in the liver development and tumorigenesis. Moreover, our work could have significant impact on the development of more effective diagnostic and therapeutic methods for liver disease.