Prostate Cancer (PrCa) constitutes a major health issue and is the second most common cause of male cancer related deaths in Australia. However, despite its prevalence, a detailed molecular understanding of prostate carcinogenesis is lacking and the discovery of novel therapeutics and biomarkers for PrCa is sorely needed. Using Genetically Engineered Mouse Models (GEMMs) of prostate cancer, and the analysis of tumours from prostate cancer patients, our laboratory has revealed a unique new molecular pathway important for human PrCa. These data indicate that abnormal levels of a set of proteins known as the Planar Cell Polarity (PCP) pathway that normally regulates the organisation and architecture of the prostate gland, may be fundamental to prostate tumour initiation and progression, and predicts for poor survival in prostate cancer patients.
We propose that alterations in PCP signalling are an important driver of human prostate cancer in initiation and progression. Understanding the key downstream effectors of PCP signalling in the prostate should provide novel therapeutic targets and markers for PrCa. Initially, we will use a new in vitro technique to culture mouse and human prostate tissue in 3D. We will culture prostate organoids from our GEMMs and molecularly characterise pathways that are regulated by PCP signalling in PrCa. Then we will extend our studies into understanding how PCP signalling impacts on the tumour microenvironment. Finally, we will use patient derived PrCa tissue samples to determine the role of core PCP components in human PrCa formation and progression. Then examine whether aberrant PCP signalling predicts for poor outcome in PrCa patients. The outcome of this work will be a detailed understanding of PCP signalling requirements in normal prostate homeostasis and PrCa. Understand how changes to PCP gene expression and localisation drive human PrCa initiation and progression. These studies will allow us to identify novel biomarkers and innovative routes for therapeutic intervention and prevention for the many men that will be affected by PrCa.