Modelling epigenetic tumour suppressor-driven urothelial carcinomas in mice

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. We will use genetic approaches to mimic the earliest steps of human bladder cancer development in the mouse bladder urothelium. Further, 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, inducible, combinatorial knockout or overexpression of genes in order to generate more accurate mouse models of bladder cancer. These model systems will be studied using genome-scale analyses of chromatin 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. The diverse experimental bladder cancer model systems will be used 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.