Coordination Funds

在德国，每年有超过3万例膀胱癌新病例，开发更好的治疗这种疾病的临床需求尚未得到满足。与其他类型的上皮性癌症不同，膀胱尿路上皮癌的特征是编码表观遗传调控蛋白的基因发生非常特定类型的复发性改变，包括功能突变丧失、染色体扩增和异常过表达。此外，这些表观遗传突变出现在肿瘤形成的早期阶段，暗示染色质可及性、染色质激活状态和DNA甲基化失调是膀胱癌的重要驱动因素。为什么这些特殊的表观遗传改变在膀胱中如此重要尚不清楚。本研究单元的实验重点是获得关于表观遗传改变如何影响膀胱尿路上皮癌形成和进展的病理过程的基本机制见解。我们进一步致力于为个体膀胱癌患者开发新的个性化、基于表观遗传学的治疗方法，以改善这种疾病的临床管理。我们提议的研究单位将建立一个研究项目，结合弗赖堡和<s:1>宾根的临床泌尿肿瘤学优势，亚琛的分子和组织病理学资源，以及弗赖堡和亚琛的基础和转化研究科学家的基础科学表观遗传学专业知识。这将在基础研究、临床研究和患者管理之间提供强有力的联系。通过密切合作，我们将基于基因工程细胞系、小鼠膀胱类器官培养、本土小鼠癌症模型，以及分子和遗传特征人类膀胱癌类器官培养的活生物库的生成和分析，产生新的尿路上皮癌模型系统。我们将在临床前翻译平台的背景下使用这些模型系统来探索尿路上皮癌表观遗传改变的遗传和化学脆弱性。同时，我们将对不同发展阶段的人类尿路上皮癌的大量档案病理样本进行分子和病理分析。这些研究将共同为膀胱癌潜在的表观遗传网络提供新的生物学理解。

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 characterized 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 personalized, 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 program 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-characterized 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.