Our Science – Thorgeirsson Website
Snorri S. Thorgeirsson, M.D., Ph.D.
Throughout his distinguished career, Dr. Thorgeirsson has established and maintained a global leadership in the field of molecular carcinogenesis, genomic classification and treatment of liver cancer. He has pioneered the use of comparative genomics for defining phenotypically homogeneous groups of HCC and is now using this knowledge as a starting point for developing and testing targeted therapies. The development of transgenic mouse models for probing the molecular pathogenesis of liver cancer is another research interest of Dr. Thorgeirsson. These models provided unexpected insights into the functionally diverse roles played by hepatic growth factors and oncogenes, and have led to effective and creative ways to answer questions fundamental to the understanding of liver cancer and the complex regulatory networks involved in stem cell activation, expansion and differentiation.
Dr. Thorgeirsson has published close to 600 journal articles, book chapters, and books, and holds more than 7 patents owned by the U.S. Government. Dr. Thorgeirsson has received the NIH Merit Award and the Distinguished Scientific Achievement Award by the American Liver Foundation, serves as an Associate Editor for Hepatology and Cancer Science, and is a member of editorial boards. Dr. Thorgeirsson has been a driving force in establishing and serves as the head of Center of Excellence in Integrative Cancer Biology and Genomics in NCI since its inception. Dr. Thorgeirsson is also a founding member of the International Liver Cancer Association (ILCA) established in 2007. He has been for a number of years the NCI representative for basic science in the US/Japan Collaborative Cancer Research Program, and has been elected member of the Icelandic and Hungarian Academy of Sciences, and the American Association for the Advancement of Science.
The research in the Cellular and Molecular Biology Section (CMBS) is focused on two projects: (A) Molecular pathogenesis, genomic classification and treatment of human liver cancer and (B) Stem cells and cancer.
Much effort is currently devoted to understanding the molecular pathogenesis, developing robust genomic classification and establishing a prognostic model for survival and treatment options of hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide. By integrating the molecular/genomics data with clinical and pathology information, we were first to demonstrate that the transcriptomic characteristics of human HCC could be used to divide tumors into two broad but distinctive subclasses that are highly associated with patient survival. These subclasses are now further divided into more homogeneous units providing an attractive source for the development of therapeutic targets for selective treatment(s).
Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy after HCC. Although overall cancer mortality has declined in the United States, the incidence of pancreatic cancer, melanoma, and liver cancer is increasing, with hepatic tumors presenting the highest frequency. Recently, we classified 104 resected CCA patients into four genomic subgroups with distinct molecular and clinical characteristics based on 5-year survival rate, time to recurrence, and the absence or presence of KRAS mutations. In the patient cohort with poor survival, we found a significant increase in receptor tyrosine kinase (RTK) expression providing the basis for developing targeted therapies in the clinical practice of CCA. We now use a translational approach integrating genomic and molecular data from our patient cohort and human CCA cell lines to assess RTKs as potential drugable targets. Our studies provide insight into the pathogenesis of cholangiocarcinoma and identify previously unrecognized subclasses of patients, based on KRAS mutations and increased levels of EGFR and HER2 signaling, who might benefit from dual-target tyrosine kinase inhibitors. Furthermore, we identified a group of CCA patients with the worst prognosis characterized by transcriptional enrichment of genes that regulate proteasome activity, indicating new therapeutic targets.
The current and future research is aimed at extending the present database of human HCC, early lesions (preneoplastic nodules) and CCA with matching clinical and pathology information to be subjected to integrated analyses of global gene expression, copy number variation, methylation and microRNA profiles as well as single nucleotide polymorphism (SNP) analysis and selective deep DNA sequencing. In addition, we recently initiated a project to test potential therapeutic targets in vivo using a mouse model of human HCC in combination with a systemic delivery of target specific siRNAs incorporated into nano-particles with the goal of expediting the clinical translation of our basic discoveries. The data derived from these approaches will help better understand the molecular pathogenesis of human HCC and to discover the most useful therapeutic targets.
For the last 16 years the CMBS has been in the forefront of establishment and application of transgenic mouse models in liver cancer research. We continue to pursue the Comparative Functional Oncogenomics which we first introduced as a novel approach to identify the best-fit mouse models to study human cancer. Through this strategy we have established a molecular relationship between mouse and human cancer and thus provided exciting new research opportunities in molecular pathogenesis, treatment and prevention of human cancer. The combined data set from our analysis of human HCC and mouse models enables us to offer a framework for investigating human liver cancer.
Despite the remarkable proliferative capacity of hepatocytes and bile epithelial cells, the adult liver contains a stem cell compartment that can be activated following injury. Our laboratory has been in the forefront of the research on adult hepatic stem cells for over two decades and made significant contributions to the current understanding of the process of liver regeneration via the stem cell compartment supported with over 60 publications on this subject. We continue to advance our understanding of the process of liver regeneration via the stem cell compartment. Our most recent and current research in this project is focused in two areas: (i) to characterize the role of c-Met and Egfr signaling pathways in the early activation and expansion of adult liver stem cells and (ii) to understand the relationship between adult hepatic stem cells and putative cancer stem cells in liver tumors. The existence and importance of cancer stem cells in cancer biology is currently hotly debated. Our central hypothesis is that cancer stem cells represent a heterogeneous population that can be generated during hepatic oncogenesis from both hepatic stem/progenitor cells and adult parenchymal cells via mutational and/or epigenetic mechanisms. We now provide evidence that diverse hepatic lineage cells from fetal and adult progenitor cells to terminally differentiated hepatocytes can be the target populations for neoplastic development and acquire a high degree of genetic similarity through activation of diverse donor cell-specific pathways. We also utilize human ES cells and induced pluripotent stem (iPS) cells to generate research material, and to employ human HCC and ICC cell lines and tissues from primary liver cancers to characterize and evaluate the importance of cancer stem cells in hepatic oncogenesis.
This page was last updated on 6/7/2013.