Analysis the Role of Adam9 as Novel Biosignature in Prostate Cancer Malignant Progression

ADAM9 has implicated increased expression in many cancer epithelial cells, including prostate, breast, renal and lung cancers, which correlated with tumor progression and distance organ metastasis. Previously, we indicated ADAM9-like protein that only expressed during disease progression (Cancer Res., 66 (19): 9519-26). Recently, our preliminary evidence indicated the soluble ADAM9 (sADAM9) could be the major ADAM9- like protein during cancer progression. We also noticed two isoforms of sADAM9, sADAM9v1 (reported by Mazzocca et al.) and sADAM9v2 (our novel finding). Interestingly, the sADAM9v2 not only can be detected in malignant prostate cancer but also in tumor-associated stromal fibroblast. Furthermore, Laser Capture Microdissection studies of prostate cancer patients indicated sADAM9v2 predominantly expressed in tumor associated stromal cells. Although the increased of sADAM9 were observed, however, the regulatory mechanisms that induced sADAM9 still not fully explored. We hypothesized that stress from the tumor microenvironment could be the mediator to induced sADAM9v2 production. The mediators could due to the elevation of ROS in the induction of sADAM9 expression. Additionally, the sADAM9 in the induction of cancer migration and invasion will be explored. Whole exosome sequence and IPA pathways studies demonstrated CCL5 could be the downstream response gene to induce cell migration. Finally, we will assess the clinical evaluation of sADAM9 and ADAM9 family as biomarker to predict prostate cancer mCRPC progression. Therefore, the purpose of this proposal is to characterize the possible mechanisms underlying sADAM9v2 expression and to determine the possibility to use the specific antibody that only detect sADAM9v2 to predict cancer progression. We will focus on three aims: 1) To analyze the role of sADAM9v2 in prostate cancer progression and metastases. The role of sADAM9 in the induction of prostate cancer bone metastasis will be analyzed in the in vitro and in vivo studies. 2) To characterize the mechanisms of sADAM9v2 to induce prostate cancer motility. We will explore the mechanisms that the environmental sADAM9v2 to induce CCL5 expression in prostate cancer cells. 3) To evaluate sADAM9v2 or ADAM9- plectin as biomarker to predict malignant prostate cancer progression. We will generate the monoclonal antibody and explore the possible to detect sADAM9v2 as biomarker to predict mCRPC progression. The novelty of this project is to determine regulation mechanisms of sADAM9v2 during progression. The objective of this project is to explore the critical mechanisms involving cancer metastasis through sADAM9v2 and prostate cancer cell interaction. The results will help us understand the molecular mechanisms involved in sADAM9v2 regulation and possibility of sADAM9v2 as biosignature to predict mCRPC progression. We hope that this proposal will provide a value information for future development of precision medicine by using ADAM9 family as target.