PROJECT SUMMARY/ABSTRACTThe most common non-cutaneous cancer in American men prostate cancer is characterized by a substantialdegree of overdiagnosis and is consequently a significant source of morbidity and driver of unnecessary cost.There is therefore a significant need to identify prostate cancer patients who need aggressive therapy comparedto those who need no treatment at all. The cancer-specific mortality of these tumors is attributable to metastaticdisease. Adenocarcinoma of the prostate must interact with smooth muscle at multiple steps of the metastaticprocess including intravasation and extravasation between the bloodstream and tissue. In addition the cancer-prone peripheral zone of the human prostate gland is composed of a fibromuscular stroma and bounded by asmooth muscle capsule. While the current paradigm for most cancers is that local invasion is not predictive ofaggressive disease this is not the case with prostate cancer. Aggressive prostate cancer cells are directlyobserved as extending past the smooth muscle capsule in clusters in a process called extracapsular extension(ECE) thereby escaping organ confinement. The presence of ECE defines the pT3a category in the pathologicstaging of prostatic adenocarcinoma and is associated with an increased risk of biochemical recurrence distantmetastases and cancer-specific mortality. Although smooth muscle invasion is required for ECE intravasationand extravasation to distant sites there are no markers of the switch from indolent to aggressive muscle-invasiveprostate cancer. This work is therefore concentrated on understanding the molecular events that regulate ECEto prevent this critical step in the metastatic process. The central hypothesis is that invasion through thesmooth muscle capsule requires unique molecular properties that predict aggressive cancer. If correctthe concept will change current standard of care by providing new molecular discriminators of indolent versusaggressive disease. Objective measures of the aggressive disease transition will inform treatment decisions andhelp to direct the appropriate level of treatment for the degree of disease aggression.