FOR 5476:  UcarE - Urothelial Carcinoma Epigenetics

• Subject Area: Medicine
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 493802833

There are more than 30,000 new cases of bladder cancer every year in Germany and there is a large unmet clinical need to develop better therapies for this disease. Unlike other types of epithelial cancers bladder urothelial carcinomas are characterised by very specific types of recurrent alterations in genes that encode epigenetic regulatory proteins, including loss of function mutations, chromosomal amplifications and aberrant overexpression. Moreover, these epigenetic mutations arise at the earliest stages of tumour formation, implicating dysregulation of chromatin accessibility, chromatin activation state and DNA methylation as important drivers of bladder cancers. Why these particular epigenetic alterations are so important in the bladder is unclear. The experimental focus of this Research Unit is to gain fundamental mechanistic insights into how epigenetic alterations affect the pathological processes that underlie bladder urothelial carcinoma formation and progression. We further aim to develop novel personalised, epigenetics-based therapies for individual bladder cancer patients to work towards improving clinical management of this disease. Our proposed Research Unit will establish a research programme that combines the strengths of clinical urological oncology in Freiburg and Tübingen, with the molecular and histopathological resources in Aachen and the fundamental scientific epigenetics expertise of basic and translational research scientists in Freiburg and Aachen. This will provide a strong link between fundamental research, clinical research and patient management. Through close collaborations we will generate new urothelial carcinoma model systems based on genetically engineered cell lines, mouse bladder organoid cultures, autochthonous mouse cancer models, and the generation and analyses of a living biobank of molecularly- and genetically-characterised human bladder cancer organoid cultures. We will use these model systems in the context of our Pre-Clinical Translation Platform to explore the genetic and chemical vulnerabilities of epigenetic alterations in urothelial carcinoma. In parallel, we will undertake molecular and pathological analyses of large collections of archival pathology samples of human urothelial carcinomas at different stages of development. These studies will collectively provide new biological understanding of the underlying epigenetic networks of bladder cancer.

• DFG Programme: Research Units

Projects

• Coordination Funds (Applicant Frew, Ian )
• P1: The impact of epigenetic dysregulation associated with mutational crosstalk on driving early bladder cancer progression (Applicant Gaisa, Nadine )
• P2: Modelling epigenetic tumour suppressor-driven urothelial carcinomas in mice (Applicant Frew, Ian )
• P3: Consequences and therapeutic vulnerabilities of KDM6A and KDM6C mutations in urothelial carcinoma (Applicant Timmers, Marc )
• P5: Dissection of KMT9 biology in urothelial carcinoma (Applicant Schüle, Roland )
• P6: Studying clinical implications of altered epigenetics using urothelial carcinoma organoid models (Applicants Gratzke, Christian ;  Stenzl, Arnulf )
• P7: Integrative molecular understanding of the epigenetics of urothelial carcinoma (Applicant Börries, Melanie )

• Spokesperson: Professor Dr. Ian Frew