Christopher Kemp

Environmental and genetic control of cancer cell evolution

The goal of our research is to understand how environmental exposure to carcinogens interacting with the genetic susceptibility of the host leads to cancer. As a basic research laboratory, we study multistage carcinogenesis in the mouse in order to model the entire natural history of neoplastic development from the initiated cell to clonal evolution to a fully malignant tumor. This has the following benefits: the influence of the host genetic background (e.g., susceptibility and resistance loci or modifier genes) can be studied; the role of particular genes can be studied using transgenic and knockout mice; somatic genetic or epigenetic changes (e.g., mutations in oncogenes and tumor suppressor genes) driving clonal neoplastic evolution and their phenotypic consequences can be studied in detail; and finally the specific effects of different carcinogen treatments on tumor development can be studied. More recently we are using mouse models of cancer to improve methods for biomarker discovery and validation using proteomics, micro RNA and other approaches for the early detection of cancer or for monitoring tumor response to therapy.

As a hallmark of the cancerous cell is loss of genetic fidelity, we are focusing on mutations in genes which control the cell cycle and/or the faithful segregation of genetic material as likely rate limiting steps. The p53 tumor suppressor gene is one such gene. It is mutated in the majority of human cancers and plays a critical role in maintaining genetic fidelity. p53 is normally induced in response to DNA damage or oncogene signaling, resulting in cell cycle arrest, senescence or apoptosis which inhibits the propagation of cells which have potentially neoplastic mutations. This pathway may also be important in the success or failure of chemo- or radio-therapy for cancer. We are addressing the following questions regarding p53 function: (1) What regulates p53 during tumor development? Our results show that oncogene signaling through p19/Arf as opposed to DNA damage signaling through Atm, is the major pathway of p53 regulation during tumor evolution. We are now pursuing how loss of p19/Arf and p53 lead to more aggressive tumors and metastatic dissemination.

We have recently shown that DNA damage can induce apoptosis in the absence of p53, and this pathway is regulated by the DNA repair enzyme DNA-PK. We are pursuing the mechanism of this novel apoptotic pathways and if this pathway can be used to increase the sensitivity of tumors to radio- or chemo-therapy.

Expression of the CDK inhibitor p27/kip1 is an important prognostic marker in almost all the major types of human cancer. Following the discovery that p27 is haplo-insufficient for tumor suppression using mouse models, we are identifying mechanisms and pathways that regulate p27 in tumors and the mechanism by which p27 regulates tumor aggressiveness. In particular we are pursuing the role of p27 in tumor metastasis.

More recent efforts in the lab are directed toward using mouse models of cancer for biomarker discovery using a comprehensive systems biology approach. Another new avenue is the role of epigenetics in dietary or radiation induced cancer and transgenerational inheritance.