Understanding the role of mitosis in the development of high-risk carcinomas

Our research goal is to understand how mitotic regulation that helps to determine stem cell function in development and tissue homeostasis, is altered in proliferative diseases such as cancer. We have focused on the role of Aurora Kinase A (Aurora-A) in normal epithelial biology and in the development of high-risk cutaneous carcinomas. Aurora-A has a fundamental role in mitosis and is frequently amplified or overexpressed in cancers including skin carcinomas. We have shown that Aurora-A overexpression in combination with the activation of the Ras oncogene or gain-of-function p53 mutants can promote keratinocyte transformation, cancer associated genomic instability and metastasis. To explore Aurora-A’s function in skin homeostasis and the potential off-tumor effects from the use of small molecule inhibitors, we have used a genetic approach to delete Aurora-A in skin epithelia of mice. Adult skin appears to better tolerate the ablation of Aurora-A unlike highly proliferative embryonic skin or tumor cells, indicating that the targeting of abnormally proliferative keratinocytes using Aurora-A inhibitors may be safe and effective. Ongoing projects will address how Aurora-A activity or protein levels are altered in early cancerous lesions and how Aurora-A co-operates with other cancer promoting events in cancer progression and metastasis. These studies will help us to evaluate therapies directed against mitotic regulators as a strategy to treat high-risk epithelial carcinomas.