Studying clinical implications of altered epigenetics using urothelial carcinoma organoid models

Recently, three-dimensional organoid culture systems of primary bladder cancer cells have been developed to overcome the limitations of cell lines and importantly to permit the direct study of patient-derived tumor samples in cell culture. Organoids are defined as 3D constructs which recapitulate many physiological characteristics of their corresponding in vivo organs, which highlights their potential for identifying therapeutic targets and verifying drug response. In this project we will utilize urothelial carcinoma organoids to study the clinical and biological implications of altered epigenetics in urothelial carcinomas, to study interactions between cancer associated fibroblasts and tumor cells and to test therapeutic responses to new epigenetically targeted therapies that will be developed by other groups in the UcarE Research Unit. To our knowledge, no organoid from metastatic bladder cancer tissue has yet been established. Using our established protocols, we aim to establish human bladder cancer organoids from both primary bladder cancer as well as from metastatic tissue. Our goal is to establish a living biobank of human bladder cancer organoid lines reflecting different stages of disease progression and encompassing different combinations of cancer driver genes, including epigenetic tumor suppressor genes. By phenotypically (histology and immunofluorescence staining), molecularly (RNA-seq) and genetically (Exome-seq) characterizing the organoids, we will establish a highly value-added urothelial carcinoma biobank that will be useful for all UcarE projects as well as more generally for the research community studying bladder cancer.