P2: Modelling epigenetic tumour suppressor-driven urothelial carcinomas in mice

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This project aims to understand how mutations in specific epigenetic tumour suppressor genes contribute to the earliest stages of development of bladder cancer, as well as to progression to invasive cancer. In a first package of work we will use genetic approaches to mimic the earliest steps of human bladder cancer development in the mouse bladder urothelium. In the second work package we will induce combinatorial genetic mutations using mouse urothelial organoid cultures as an experimental system in order to mimic the complex combinatorial genetic alterations in epigenetic tumour suppressor genes and in other oncogenic pathways that arise in human bladder cancer. In a third aim, we will develop a new experimental system to allow the rapid generation of lines of mice that allow the cell type-specific, doxycycline-inducible, combinatorial knockout or overexpression of genes in order to generate more accurate mouse models of bladder cancer. All of these model systems will be studied using a series of genome-scale analyses of chromatin binding, chromatin modification and RNA transcription to gain molecular insight into how mutations in epigenetic tumour suppressor genes lead to bladder cancer formation. We will also use our model systems in chemical library and genetic library screening studies to identify, and test, new therapeutic opportunities that exploit vulnerabilities resulting from specific mutations in epigenetic tumour suppressor genes. Close interactions with all of the other UcarE projects will permit translation of the findings made in our mouse studies to human bladder cancer samples, organoids and cell lines. The diverse experimental bladder cancer model systems that will be generated in this project will in turn be very useful for several other UcarE projects to allow investigation of insights made through the study of human cellular systems in the physiological context of the mouse bladder, and will provide experimental models for pre-clinical therapeutic testing.