PROJECT SUMMARY - U01CA225784 Prostate cancer (PCa) is one of the most prevalent forms of malignancy and the second most common cause of cancer-related death in men. Uncovering novel mechanisms that control prostatic tumorigenesis may advance development of more effective therapeutics to treat this life-threatening disease. Heparan sulfate (HS), a type of polysaccharide, is an essential component of the cell microenvironment and plays an important role in cell-cell and cell-matrix interaction and signaling. Recent studies reported that expression of HS-synthesizing and modifying genes are dysregulated in human PCa specimens. Currently, it is not known what causes this aberrant HS expression, and, more importantly, what are the functional consequences of the aberrant HS expression in prostatic tumorigenesis. In this application, we propose to test our novel hypothesis “Pten-loss in prostate leads to aberrant HS expression creating a unique cellular environment that potentiates prostatic tumorigenesis” by pursuing the following three Specific Aims: 1. Determine if aberrant HS expression in human prostate epithelial cells is induced by Pten-loss and correlates with malignancy of Pten- null human PCa; 2. Determine if aberrant HS expression induced by Pten-loss potentiates prostatic tumorigenesis; 3. Determine if aberrant HS expression induced by Pten-loss potentiates PCa-associated inflammation. The proposed studies will use both novel and established genetic, cellular, biochemical and bioinformatics approaches in conjunction with in vitro cell function and in vivo human and mouse PCa models. These serial investigations are anticipated to delineate a novel mechanism that drives aberrant HS expression in PCa, reveal the aberrant HS expression to be a novel biomarker for PCa early diagnosis and prognosis, and elucidate the pivotal roles and their underlying molecular mechanisms of the aberrant HS expression in prostatic tumorigenesis, which likely will contribute to the development of novel therapeutics for PCa treatment.