Grant: Project Grant

Prostate cancer is one of the most common and most deadly cancers in males. Over the years, research has mostly focused on the identification of treatments against advanced forms of prostate cancer. In this grant proposal, we rather aim to understand the cellular environment that promote cancer initiation, to eventually devise preventative treatments aimed at maintaining a healthy prostate tissue organization. Such approach is not currently available for prostate cancer. Our recent results in mouse models show that when the cells of the prostate divide in the plane of the tissue (horizontal), they maintain a proper tissue architecture made of one layer of basal cells and one layer of luminal cells. However, when the cells divide vertically, they create an aberrant layer of cells that lose their polarity, proliferate more and harbor stem/progenitor cell characteristics. We believe that this cellular environment promotes the birth and growth of tumor initiating cells. Here, we will study how cells defective in the orientation of cell divisions generate this abnormal cell population and will identify new regulators that promote vertical divisions. We will also generate cancer initiating cells (single cells missing the tumor suppressor Pten) and identify the detailed characteristics in the cellular environments that promote their growth. We expect the normal prostate epithelium to suppress cancer initiation but the aberrant depolarized cell populations to promote it. We will corroborate our results in premalignant human tissues obtained from our clinical collaborators and link these results to disease outcome. Together these results will greatly advance our understanding of oriented cell division and the maintenance of tissue architecture. More importantly, it will identify the characteristics of premalignant lesions that are associated with cancer initiation and progression. These results will be critical to develop interventions aimed at preventing prostate cancer.