Mouse models for hepatocellular carcinoma and liposarcoma

Another major effort in the laboratory is to develop mouse models that would recapitulate the human cancer conditions as best as possible, using state-of-the-art genetic engineering technology. This will enable the identification of novel biomarkers for early detection, as well as potential molecular targets for timely-intervention. In this regard, we have been working on modelling hepatocellular carcinoma (HCC), and liver fibrosis, and have generated mouse models that recapitulate human HCC, both molecularly and histologically. Moreover, we have established the liver fibrosis model in mice, and are now interrogating the critical aspects of the fibrotic process. We have focused on c-Jun, the major transcription factor of the Activator-Protein-1 family, which is a key regulator of liver development and pathology, through its deletion in multiple cell types of the liver in mouse models.

Other efforts are also ongoing to establish mouse models for liposarcoma (LPS) - tumors that arise from fat cells (adipocytes) in soft tissues. Though surgery is the main mode of treatment for LPS, the understanding of this disease is limited due it being not a common cancer, and hence, treatment modalities have been restricted. While the process of adipogenesis has been well studied, knowledge of the transformation of an adipocyte to liposarcomas is limiting due to the lack of effective model systems to study the development and progression of this disease. Mdm2, the negative regulator of the tumor suppressor p53, is often amplified in all types of sarcomas. Thus, we are generating mouse models in which selective genetic changes are introduced in the germ-line conditionally to follow the transformation of the adipocytes, which will provide a paradigm for studying the biology of liposarcomas, and could open up new opportunities for treatment. In this context, the role of c-Jun is also being investigated in adipogenesis and insulin resistance.