We have identified the serine protease PRSS3/mesotrypsin as a molecule that is prognostic for prostate cancer systemic progression following prostatectomy, and that is upregulated in metastatic prostate cancer tissue. We have also found that silencing of mesotrypsin expression in prostate cancer cells inhibits invasiveness in culture and metastasis in an orthotopic mouse model, while treatment of prostate cancer cells with recombinant mesotrypsin stimulates invasive behavior. Our preliminary data suggest that mesotrypsin promotes prostate cancer progression through cleavage of one or more specific substrates in the extracellular matrix (ECM), leading to upregulation of COX-2 and stimulation of invasive behavior. We hypothesize that mesotrypsin may represent both a potential therapeutic target for metastatic prostate cancer and a useful prognostic tissue biomarker of systemic progression. Here, we propose experiments (1) to further define the biological mechanisms by which mesotrypsin promotes prostate cancer progression, (2) to develop potent and selective mesotrypsin inhibitors that will facilitate mechanistic studies in culture and animal models and offer candidates for mesotrypsin-targeted therapeutics, and (3) to evaluate mesotrypsin as a prognostic tissue biomarker.
In Aim 1, we will identify proteolytic substrates of mesotrypsin in ECM using a proteomic approach, and test their impact on invasion using 3D culture models. We will also determine the mechanisms by which mesotrypsin regulates COX-2 transcription using promoter-reporter assays and RNA interference approaches.
In Aim 2, we will employ structure-guided protein engineering to optimize a polypeptide inhibitor of mesotrypsin, and evaluate the impact of this inhibitor on invasion in culture assays and on tumor growth and metastasis in an orthotopic mouse model.
In Aim 3, we will assess mesotrypsin protein staining as a potential prognostic tissue biomarker in a high-risk radical prostatectomy cohort, using a newly developed selective mesotrypsin antibody. We will also determine whether mesotrypsin expression is associated with metastasis to specific organ sites, using a diverse panel of metastatic tissues. The successful completion of these aims will critically improve our understanding of novel molecular mechanisms that underlie prostate cancer progression.
Prostate cancer is the second leading cause of cancer death in men, and metastasis, the spread of cancer from the primary tumor to other organs, is the main cause of death. We have identified mesotrypsin as an enzyme involved in the spread of prostate cancer. By learning more about the role of mesotrypsin in prostate cancer progression, by creating drugs that target mesotrypsin function, and by developing ways to measure mesotrypsin in prostate cancer tissue, we hope to develop new therapies for treating prostate cancer and new prognostic tests to guide treatment strategies for prostate cancer survivors.
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|Alloy, Alexandre P; Kayode, Olumide; Wang, Ruiying et al. (2015) Mesotrypsin Has Evolved Four Unique Residues to Cleave Trypsin Inhibitors as Substrates. J Biol Chem 290:21523-35|
|Mehner, Christine; Oberg, Ann L; Kalli, Kimberly R et al. (2015) Serine protease inhibitor Kazal type 1 (SPINK1) drives proliferation and anoikis resistance in a subset of ovarian cancers. Oncotarget 6:35737-54|
|Mehner, Christine; Hockla, Alexandra; Miller, Erin et al. (2014) Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer. Oncotarget 5:2736-49|
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