The group’s main research interests have been the elucidation of the genetics and biology of multistage carcinogenesis, with particular emphasis on mouse models of chemically induced skin tumor development. The skin model system is ideally suited to studies of the role of tissue stem cells in cancer, because of the wealth of information available on the location and characteristics of skin stem cells. Our strategy has been to identify the target cells for mutation in the skin, and subsequently to elucidate the sequence of somatic genetic alterations which are associated with discrete stages of tumorigenesis: initiation, promotion, progression, metastasis. In each case where a genetic change has been identified, we have attempted to address the question of causality by making extensive use of transgenic or knock-out mice, and to investigate the biological consequences of this genetic change for cell behavior during transformation. The results have shown that the kinds of genetic and biological alterations seen in mouse tumors are very similar to what is observed in human malignancies, thus providing strong evidence that the mouse is a uniquely appropriate model for the development of cancer in humans. A major emphasis has been on the study of cancer susceptibility, and the relationships between germline polymorphisms that increase risk, and the somatic genetic events involved in tumour progression. The skin model system has enabled us to begin to study the role of stem cells in cancer development and progression. Genetic approaches have identified specific genes and polymorphisms that control the cancer stem cell fate decision, and thus contribute to individual cancer susceptibility.
We are presently extending our studies on skin carcinogenesis to other mouse model systems for tumor development in the lung, prostate and lymphoid system. The goal for the next few years is to exploit mouse model systems for the identification of genes that are important for cancer susceptibility or cancer progression in human populations, as a route to the discovery of novel diagnostics, new possibilities for prevention, or therapeutics.