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Ruth Fuhrman-Luck Thesis (PDF 6MB) DETERMINING THE KALLIKREIN- RELATED PEPTIDASE 4-REGULATED TRANSCRIPTOME AND DEGRADOME IN THE PROSTATE TUMOUR MICROENVIRONMENT Ruth Anna Fuhrman-Luck BAppSc(Hons) Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Institute of Health and Biomedical Innovation Faculty of Health School of Biomedical Sciences Queensland University of Technology May 2015 Keywords Cancer, degradome, degradomics, fibroblast, kallikrein-related peptidase, microenvironment, myofibroblast, omics, peptidase, prostate, protease, proteomics, reactive, stroma, substrate, transcriptome, transcriptomics, transforming growth factor, tumour. i ii Abstract Prostate cancer is the third-leading cause of male cancer-related deaths in developed countries. Prostate cancer-associated mortality ensues when the cancer spreads to other organs, primarily bone. Novel therapies are required to inhibit prostate cancer development and progression to malignant disease. While it is the gland-lining or epithelial cells of the prostate that become malignant, these cells must activate the surrounding microenvironment to facilitate disease progression. As such, future anti- cancer therapies should target factors that drive development of the tumour and activation of its microenvironment. Kallikrein-related peptidase 4 (KLK4) is a prostate epithelial cell-secreted protease, which is over-produced in prostate cancer and in a pre-cancerous pathology whereupon activation of the tumour microenvironment is believed to initiate. The pattern of expression of KLK4 in prostate pathologies suggests that it may function in prostate cancer progression. A small number of functional studies performed to date have shown that KLK4 induces prostate cancer cell motility and transformation to a migratory phenotype, each of which precedes the spread of localised disease and metastasis. However, knowledge of KLK4 function in the surrounding tumour microenvironment is limited. A greater understanding of KLK4 function in prostate cancer and its microenvironment is required to evaluate the utility of KLK4 as an anti-cancer target. To this end, the present study aimed to use high-depth techniques to identify the pool of cell-secreted KLK4 substrates (its degradome) and KLK4-regulated genes (its transcriptome) in prostate cancer cells and the tumour microenvironment. This work comprises the most extensive omics analyses of KLK4 function to date. Previously, KLK4-mediated regulation of only a handful of genes had been assessed. Herein, a iii gene microarray platform was employed to assess KLK4-regulated expression of ~20,047 genes. Further, while some KLK4 substrates are known, each has been generally selected for screening based on a priori association to cancer, thus conferring a literature bias on substrate identification. Moreover, individual substrates have been screened by incubation with KLK4 in a test tube, making it difficult to ascertain whether KLK4 can cleave each protein in the complex, protein- rich tumour microenvironment. The PROtein TOpography and Migration Analysis Platform (PROTOMAP) approach employed herein overcomes these shortcomings, being a low-bias, high-depth technique allowing for simultaneous determination of all detectable protein cleavage events within a cell-derived protein pool. The KLK4 degradome was first delineated in secretions from LNCaP and PC-3 prostate cancer cells, representative of early- and late-stage disease, respectively. Twenty-nine novel KLK4 substrates were identified, as well as one established substrate, urokinase-type plasminogen activator (uPA), which served to validate the approach. Matrix metalloproteinase-1 (MMP1) was biochemically validated to be activated by KLK4, and in vitro validation was also performed for KLK4-mediated hydrolysis of granulin (GRN) and vinculin (VCL/VINC). These and other of the novel KLK4 substrates identified have been functionally implicated in tumour- promoting processes. Such processes include cell migration and blood vessel formation, which are established and novel putative KLK4-regulated functions, respectively. Surprisingly, transcriptome analyses revealed only three genes to be KLK4-regulated in prostate cancer cells, indicating that KLK4 activity does not have a major autocrine effect on prostate cancer cell function at the level of gene expression, at least under the conditions employed. iv The above finding led to the supposition that KLK4 may instead have more extensive regulatory effects on other cell types within the prostate tumour microenvironment. In particular, prostate cancer cells secrete factors that stimulate the activation of resting fibroblasts to a tumour-promoting or activated phenotype. Activated fibroblasts, in turn, signal to neighbouring epithelium to permit and support tumour progression. This process begins in the pre-cancerous prostate pathology in which KLK4 is first up-regulated. Thus, KLK4 is well-positioned to act on prostate fibroblasts to regulate fibroblast activation and resulting tumour-inductive signalling. The KLK4-regulated transcriptome was next assessed in the prostate WPMY-1 myofibroblast cell line, used to represent tumour-adjacent fibroblasts. KLK4 regulated 439 genes, with pathway analysis tools identifying transforming growth factor beta-1 (TGFβ1) as a significant mediator of KLK4-regulated transcription. Accordingly, genes up- and down-regulated by KLK4 in WPMY-1 myofibroblasts were similarly regulated by TGFβ1 (Fisher’s exact test, P ≤ 0.01). TGFβ1 signalling in activated or cancer-associated fibroblasts (CAFs) promotes an aggressive cancer phenotype, suggesting that KLK4 may favour prostate cancer progression via induction of TGFβ1 signalling in CAFs. Analysis of the KLK4 degradome identified 50 novel WPMY-1 myofibroblast-derived substrates, including 11 known to regulate TGFβ1 activity. Of these, KLK4 appeared to cleave latent-transforming growth factor beta-binding protein 4 (LTBP4) and fibrillin-1 (FBN1) in a manner likely to induce TGFβ1 activity, demonstrating a plausible proteolytic mechanism for KLK4- mediated activation of TGFβ1 signalling in the prostate tumour microenvironment. This study constitutes the most comprehensive analysis of the KLK4-regulated transcriptome and degradome in prostate cancer to date, and is the first such analysis of KLK4 action within the prostate tumour microenvironment. The results obtained v affirm KLK4 as a promising anti-cancer target, suggesting that KLK4 inhibition may reduce pro-tumourigenic signals from the prostate tumour microenvironment, a critical component of prostate cancer progression. vi Table of Contents Keywords ...................................................................................................................... i Abstract ....................................................................................................................... iii Table of Contents ....................................................................................................... vii List of Tables............................................................................................................. xiv List of Figures ............................................................................................................ xv List of Abbreviations............................................................................................... xviii Statement of Original Authorship ............................................................................ xxv List of Publications and Awarded Presentations ..................................................... xxvi Acknowledgements ................................................................................................ xxvii Chapter 1: Introduction and Literature Review ..................................................... 1 1.1 Prostate cancer epidemiology, treatment and aetiology ..................................... 3 1.1.1 Prostate cancer epidemiology and treatment ............................................. 3 1.1.2 Prostate cancer aetiology ........................................................................... 3 1.1.3 Proteases as targets for cancer therapy ...................................................... 4 1.2 KLKs and prostate cancer ................................................................................... 6 1.2.1 PSA as a widely-employed prostate cancer biomarker ............................. 7 1.2.2 Other KLKs implicated in prostate cancer pathogenesis .......................... 7 1.2.3 Targeting KLK expression and activity in the clinic ................................ 9 1.3 Functional characterisation of KLK activity and post-translational regulation 10 1.3.1 Proteolytic activity and specificity .......................................................... 11 1.3.2 Post-translational regulation .................................................................... 12 1.4 KLK function in healthy adult biology ............................................................. 13 1.4.1 KLK function in seminal fluid and prostate tissue .................................. 13 1.4.2 KLK function in tooth enamel maturation .............................................. 15 1.5 In vivo studies of KLK function in prostate cancer .......................................... 16 1.6 In vitro studies of KLK function in prostate cancer ......................................... 18 1.6.1 KLK function in tumour proliferation ..................................................... 19 1.6.2 KLKs and migration ...............................................................................
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