Epigenetic regulators of subtype plasticity in bladder cancer

项目总结/摘要 膀胱癌可以分为两类：非肌肉浸润性膀胱癌（NMIBC）和 肌肉浸润性膀胱癌（MIBC）。NMIBC通过经尿道切除术治疗，然后进行 膀胱内免疫治疗或膀胱内化疗，其10年疾病特异性生存率为 百分之七十五相比之下，MIBC的标准治疗是根治性化疗联合辅助治疗或新辅助治疗。 化疗，疾病特异性生存率低得多。然而，大约20%的高- 级NMIBC将进展为MIBC，正在进行的研究无法确定分子 这一NMIBC-MIBC转变的机制。基于来自患者源性膀胱的分析的最新数据， 肿瘤类器官，我们提出，NMIBC是倾向于进展是表观遗传不同于稳定NMIBC 并通过谱系可塑性机制转变为MIBC。具体地说，建立了一个类器官的子集， 从管腔NMIBC肿瘤在培养中经历表型转换为基底/鳞状表型， 更典型的是MIBC。分析染色质可及性的初步研究表明，这些表型 塑料患者衍生的类器官（PDO）在表观遗传学上不同于表型稳定的PDO。 此外，靶向表型可塑性类器官系中的表观遗传调节因子的化学筛选， 揭示了一个控制表型可塑性的关键途径。 基于表型可塑性和表观遗传调节因子促进基因突变的假设， NMIBC到MIBC，这个拟议的项目将追求两个具体目标：（1）绘制染色质可及性和 NMIBC中表型可塑性组蛋白修饰景观并在人类患者中验证这些发现 样品，和（2）测试在化学筛选中鉴定的表观遗传调节剂是否可以调节可塑性 并确定这些调节因子是否是潜在的新治疗靶点。结合起来， 这两个目标将有助于更好地预测哪些高等级的非物质基础型生物体将发展为物质基础型生物体， 用于治疗高级别NMIBC的治疗剂。

Project Summary/Abstract Bladder cancer can be subdivided into two categories: non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). NMIBC is treated by transurethral resection followed by either intravesical immunotherapy or intravesical chemotherapy, which have a 10-year disease-specific survival of 75%. In contrast, standard of care for MIBC is radical cystectomy with either adjuvant or neoadjuvant chemotherapy, with much lower disease-specific survival. However, approximately 20% of patients with high- grade NMIBC will progress to MIBC, and ongoing studies have been unable to determine the molecular mechanisms of this NMIBC-MIBC transition. Based on recent data from analyses of patient-derived bladder tumor organoids, we propose that NMIBC that is prone to progress is epigenetically distinct from stable NMIBC and transitions to MIBC through a mechanism of lineage plasticity. Specifically, a subset of organoids established from luminal NMIBC tumors undergo a phenotypic switch in culture to a basal/squamous phenotype, which is more typical of MIBC. Preliminary studies analyzing chromatin accessibility indicate that these phenotypically plastic patient derived organoids (PDOs) are epigenetically distinct from phenotypically stable PDOs. Furthermore, a chemical screen targeting epigenetic regulators in the phenotypically plastic organoid lines has revealed a key pathway governing phenotypic plasticity. Based on the hypothesis that phenotypic plasticity and epigenetic regulators promote the transition of NMIBC to MIBC, this proposed project will pursue two specific aims: (1) Map the chromatin accessibility and the histone modification landscape of phenotypic plasticity in NMIBC and validate these findings in human patient samples, and (2) Test whether the epigenetic regulators identified in a chemical screen can modulate plasticity in bladder cancer and determine whether these regulators are potential novel therapeutic targets. Combined, these two aims should lead to improved prediction of which high-grade NMIBCs will progress to MIBC and new therapeutics for treatment of high-grade NMIBC.