Research Goals of the Cellular and Molecular Biology Section

The goal of the research program in the Cellular and Molecular Biology Section (CMBS) is to apply an integrated approach encompassing cellular and molecular biology, genetics, genomics and bioinformatics to address biological questions. Our current research is focused on two major areas:

1. characterization of the multistage process of liver carcinogenesis and
2. hepatic stem cell biology.

Hepatocellular carcinoma (HCC) is one of the most frequent neoplasms worldwide, with over four hundred thousand new cases and almost as many deaths each year. Hepatocarcinogenesis in humans, like most non-hereditary cancers, is a slow process. The emergence of HCC occurs following the appearance of a series of preneplastic liver lesions and coincides with accumulation of irreversible alterations in a number of genes and chromosomes. Although much is known about both the cellular changes that lead to HCC and the etiological agents responsible for the majority of HCC, the molecular pathogenesis of HCC, in particular the sequence of genetic alterations that drive the development of liver neoplasm, is not understood.

We have used two approaches to elucidate the molecular pathogenesis of HCC:

1. generated a series of transgenic mouse models (employing both gene additions and deletions) that reproducibly produce liver cancer to study the cellular, cytogenetic and genetic alterations that occur during the sequential development of the liver tumors. Also, we have established cell lines from the mouse liver tumors, and
2. acquired a large collection of human liver tumors with corresponding samples of non-tumorous liver tissue as well as human HCC derived cell lines. These resources are currently being used in studies on genetics and genomics of liver cancer including the application of gene and tissue expression arrays.

It has been known for centuries that the adult mammalian liver has a unique capacity to regenerate following loss of tissue mass from the remaining healthy hepatocytes and bile epithelial cells. However, it is only recently that it has been firmly established that the adult liver also contains a dormant multipotential stem cell compartment that can regenerate the liver under conditions in which the hepatocytes are incapable of responding to the regenerative stimuli. Progenitor cells derived from the hepatic stem cell compartment are ideal targets for gene and cell transplantation therapies for liver diseases. In order to realize the therapeutic potential of hepatic stem cells as well as to understand their role in tissue homeostasis, this lab seeks to define the mechanisms regulating lineage commitments of these cells during regeneration.

The current research is primarily being done in rat liver and is focused on

1. defining the growth factor/receptor systems that are critical in the activation, expansion and differentiation of hepatic stem cells in vivo, and
2. establishing an in vitro model system for detailed analysis of the mechanisms of lineage commitment and differentiation of the liver stem cells.