Epigenetic regulators of subtype plasticity in bladder cancer

项目摘要/摘要 膀胱癌可分为非肌肉浸润性膀胱癌和非肌肉浸润性膀胱癌 肌肉浸润性膀胱癌(MIBC)。NMIBC的治疗是经尿道电切，然后是 膀胱内免疫治疗或膀胱内化疗，其疾病特异性生存期为10年 75%。相比之下，对MIBC的标准治疗是根治性膀胱切除术，辅以辅助或新辅助治疗。 化疗，特定疾病的存活率要低得多。然而，大约20%的高- NMIBC级将进展到MIBC，正在进行的研究一直无法确定分子 这种NMIBC-MIBC转变的机制。基于对患者来源的膀胱的最新分析数据 肿瘤类物质，我们认为易进展的NMIBC在表观遗传学上有别于稳定的NMIBC 并通过谱系可塑性机制转变为MIBC。具体地说，有机化合物的一个子集建立了 从腔内NMIBC肿瘤在培养中经历表型转换为基础/鳞状表型，这是 更典型的MIBC。分析染色质可及性的初步研究表明，这些表型 塑料患者衍生器官(PDO)在表观遗传学上不同于表型稳定的PDO。 此外，针对表型塑料类器官系中的表观遗传调节因子的化学筛选已经 揭示了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 从NMIBC到MIBC，这个拟议的项目将追求两个具体目标：(1)绘制染色质的可及性和 NMIBC表型可塑性的组蛋白修饰图谱，并在人类患者中验证这些发现 样本，以及(2)测试在化学筛选中确定的表观遗传调节因子是否可以调节可塑性 并确定这些调节剂是否为潜在的新治疗靶点。加在一起， 这两个目标应该会改善对哪些高级别NMIBCs将发展到MIBC和新的 治疗高级别NMIBC的方法。

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.