Lineage Analysis of Cells of Origin for Prostate Cancer

I propose the Prostate Cancer Training Award project titled 'Lineage Analysis of Cells of Origin for Prostate Cancer' with the following career goals: To become an independent prostate cancer researcher and to establish my own laboratory where mechanisms of prostate cancer progression are revealed and translated into clinical diagnosis and personalized therapy. The Herbert Irving Comprehensive Cancer Center of Columbia University Medical Center provides an ideal training environment to support me in attaining these goals. This includes a world-renowned team of leaders in prostate cancer research, state-of-the-art facilities, and an atmosphere encouraging collaborations, discussions, and mutual learning. Under the mentorship of Dr. Michael Shen, who is an authority in studying prostate cancer initiation, I will conduct the proposed project, which is designed to expose me to the broad knowledge, significant ideas, and latest methodologies in prostate cancer research. The work done in this proposal will lay a solid foundation for my future independent investigations.

My research interests come from the finding that prostate pre-cancerous lesions can occur frequently at a young age but not all lesions progress into clinically lethal disease. Distinguishing lethal from indolent prostate cancer at an early stage will clearly benefit the patients. However, which factors account for the different disease symptoms are largely unknown. Since each lesion occurs due to specific genetic mutations in specific cells, different cells of origin for prostate cancer may represent the basis for the different disease outcomes. A cell of origin is essentially a normal tissue cell from which the occurrence of genetic mutations can lead to cancer. The objective of this proposed project is to investigate (1) what are the cells of origin for prostate cancer, with a focus on the basal cells in the prostate epithelium since they are abundant but the least studied, and (2) whether we can link specific cells of origin to specific prostate cancer disease outcomes. These objectives will be achieved by applying a novel technique called lineage analysis on mouse prostate cancer models, which introduces defined genetic mutations to basal cells or others in the prostate and monitor their contribution to cancer development in live animals.

This study addresses basic biological mechanisms of prostate cancer progression, but can be potentially very informative for distinguishing different prostate cancer symptoms in the clinics. In particular, it will tell us which cells in the prostate and which genetic pathways in those cells are more susceptible to cancer transformation and can more easily progress into a deadly disease. If successful, in two years time, novel molecular markers may be identified to distinguish different types of prostate cancer in mouse at each tumor developmental stage. These markers can then be validated in human clinical studies. By linking those validated markers to specific disease outcomes, it will be possible to diagnose patients with potential lethal cancer lesions at an early stage, thereby greatly reducing death and suffering later.

In addition to the above potential clinical benefits, this study will also represent a significant advancement in the research field of prostate cancer progression. Most current studies in this area do not distinguish different cells of origin for prostate cancer. But, in reality, cancer initiates from only a tiny subpopulation of cells. By developing next-generation mouse models that incorporate lineage analysis, this study sets an example on modeling cancer development in real life and dissecting the role of specific cells in this process. Future research using this approach will surely further elucidate the molecular and cellular mechanisms of prostate cancer initiation and progression.