Experimental Tumor Pathology
The main research focus of the Department of Experimental Tumor Pathology (Head: Prof. Dr. med. D. F. Calvisi) is the molecular pathogenesis of liver tumors as well as the generation of innovative therapies against cancer.
Liver cancer is the fifth most common tumor and the second leading cause of cancer related deaths worldwide. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the predominant primary hepatic tumors in the adult, whereas hepatoblastoma (HBL) is the most frequent liver pediatric neoplasia. Regardless of the histologic type, liver tumors are highly aggressive malignancies with very limited treatment options when they cannot be surgically resected. This is mainly because the molecular mechanisms responsible for liver carcinogenesis remain poorly understood.
Our research group is involved in the investigation of the functional interplay of various signaling pathways (AKT/mTOR, Ras/MAPK, Hippo, Notch, Wnt/Beta-catenin, etc.) in the three liver tumor types in terms of tumor development, progression, and response to innovative (molecularly-based) therapies. In particular, we are focusing on the importance of tumor metabolism in liver malignant transformation and support of tumor growth. Mounting evidence in fact indicates that metabolic reprogramming is one of the hallmarks of cancer. In this regard, we are involved principally in the elucidation of the role played by aberrant lipogenesis and its major regulator, fatty acid synthase (FASN), in tumors. We are intensively investigating the molecular mechanism that render cancer cells (not limited to the liver) sensitive or resistant to fatty acid depletion and the cellular/molecular consequences of lipogenesis deregulation. Furthermore, we are studying new ways to effectively kill cancer cells and induce tumor growth delay or inhibition. The importance of therapies being able to target specific molecular alterations in cancer cells is becoming more and more apparent. This is particularly relevant for tumors such as HCC, CCA, and pancreatic cancer, which only minimally respond to the available chemotherapeutic treatments. Thus, our group is investigating the way to specifically target the mechanisms involved in tumor uncontrolled proliferation and low programmed cell death as well as on drug resistance.
To better understand the role of oncogenes and tumor suppressor genes as well as their functional interplay in cancer in vivo, we take advantage of the hydrodynamic tail vein gene delivery technology. This technique consists in the injection of high amount of naked DNA containing the gene (or genes) of interest in the mouse lateral tail vein, leading to stable overexpression of the gene(s), which is mediated by the sleeping beauty transposase in the target tissues (mainly hepatocytes in the liver). The use of the hydrodynamic technique has so far allowed us and our collaborators to make seminal discoveries on various aspects of liver tumorigenesis, including tumor differentiation, signal transduction, cell lineage plasticity, resistance to therapy, etc.
The results obtained by hydrodynamic gene delivery are substantiated in human cell lines derived from HCC and CCA patients as well as in a collection of human HCC and CCA specimens.