P6: Studying clinical implications of altered epigenetics using urothelial carcinoma organoid models

最近，已经开发了原代膀胱癌细胞的三维类器官培养系统，以克服细胞系的局限性，并且重要的是允许在细胞培养中直接研究患者来源的肿瘤样品。类器官被定义为3D构建体，其概括了其相应的体内器官的许多生理特征，这突出了其用于鉴定治疗靶点和验证药物反应的潜力。在这个项目中，我们将利用尿路上皮癌类器官来研究尿路上皮癌中表观遗传学改变的临床和生物学意义，研究癌症相关成纤维细胞和肿瘤细胞之间的相互作用，并测试对UcarE研究单位其他小组开发的新表观遗传靶向疗法的治疗反应。据我们所知，尚未建立来自转移性膀胱癌组织的类器官。使用我们建立的方案，我们的目标是从原发性膀胱癌以及转移性组织建立人膀胱癌类器官。我们的目标是建立一个人类膀胱癌类器官系的活体生物库，反映疾病进展的不同阶段，并包含癌症驱动基因的不同组合，包括表观遗传肿瘤抑制基因。通过表型（组织学和免疫荧光染色），分子（RNA-seq）和遗传（Exome-seq）表征类器官，我们将建立一个高附加值的尿路上皮癌生物库，该生物库将用于所有UcarE项目以及更普遍的研究膀胱癌的研究社区。

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.