Modeling bladder cancer pathogenesis and tumor evolution

项目摘要/摘要： 这一新的计划项目将研究糖尿病发病的分子机制。 膀胱癌。我们的目标是：(I)研究从非肌肉侵袭性到侵袭性到 转移性疾病，并阐明每个进化阶段的分子驱动因素； 研究其作用机制 疾病发病机制，主要关注影响表观基因组的突变的功能作用； 阐明疾病反应和抗性的机制，重点是了解那些 影响对化疗的反应；以及(Iv)产生新的人类患者来源和基因工程 建立小鼠模型(GEMM)以研究疾病的发病机制并进行联合临床研究。要实现 为了实现这些目标，我们在哥伦比亚大学组建了一支成就卓著的多学科团队 医疗中心(科里·阿巴特-申、迈克尔·沈、詹姆斯·麦基尔南、田正)和斯隆纪念馆 凯特琳癌症中心(David B.Solit，Hikmat Al-Ahmadie，Barry Taylor)在以下方面具有互补的专业知识 基因组分析(DBS，HA，Bt)，分子研究(CAS，MS，DBS)，治疗反应(CAS，MS， DBS，JM，BT)，生物统计学和生物信息学(TZ，BT)，分子病理学(HAA)，人类和 小鼠肿瘤模型(CAS，MS)，联合临床和临床研究(DBS，JM，CAS，JM，MS)。 我们将推进三个相互关联的项目，这些项目得到三个核心的支持。项目1，由David领导 Solit将寻求确定组蛋白去甲基酶KDM6A在膀胱癌中的生物学功能 发病机制，以及在肿瘤进展过程中该基因突变的时间发生。项目 2将分析染色质重塑基因ARID1a在肌肉中的功能。 浸润性膀胱癌在疾病发病机制中的作用及其对治疗反应的影响 分子作用机制。由Michael Shenin领导的项目3将研究肿瘤的进化和药物 关注基因组遗传决定因素的人膀胱癌有机体的反应 不稳定，表观基因组的改变，以及异质性在药物敏感性和耐药性中的作用。这个 由Hikmat Al-Ahmadie领导的分子病理学核心(核心A)将维护尿路上皮的生物储存库 癌症，包括用于生成有机物的组织，并将提供组织病理学分析 所有这三个项目。由Michael Shenin领导的膀胱癌模型核心(核心B)将作为中心 为所有三个项目生成和分析癌症模型的中心，包括人类患者来源的项目 有机体和异种移植模型，以及GEMM。由科里·阿巴特-申领导的行政核心(核心C)将 为生物信息和生物统计分析提供支持，并为计划项目提供组织支持 调查人员，将与内部和外部咨询委员会协调。总而言之，这一计划 该项目由一个高度协作的调查团队领导，他们拥有不同但互补的专业知识 在癌症研究方面有丰富的记录，并且位于纽约市附近。

Project Summary/Abstract: This new Program Project will investigate the molecular mechanisms underlying the pathogenesis of bladder cancer. Our objectives are: (i) to study clonal evolution from non-muscle invasive to invasive to metastatic disease, and to elucidate molecular drivers for each stage of evolution; (ii) to study mechanisms of disease pathogenesis, with a major focus on the functional role of mutations that affect the epigenome; (iii) to elucidate mechanisms of disease response and resistance, with a major focus on understanding those that affect response to chemotherapy; and (iv) to generate novel human patient-derived and genetically-engineered mouse models (GEMMs) to study disease pathogenesis and to pursue co-clinical investigations. To achieve these objectives, we have assembled a highly accomplished multi-disciplinary team at Columbia University Medical Center (Cory Abate-Shen, Michael Shen, James McKiernan, Tian Zheng) and Memorial Sloan Kettering Cancer Center (David B. Solit, Hikmat Al-Ahmadie, Barry Taylor) with complementary expertise in genomic analyses (DBS, HA, BT), molecular investigations (CAS, MS, DBS), treatment response (CAS, MS, DBS, JM, BT), biostatistics and bioinformatics (TZ, BT), molecular pathology (HAA), generation of human and mouse cancer models (CAS, MS), co-clinical and clinical investigations (DBS, JM, CAS, JM, MS). We will pursue three interrelated Projects that are supported by three Cores. Project 1, led by David Solit, will seek to define the biologic functions of the histone demethylase, KDM6A, in bladder cancer pathogenesis, as well as the temporal occurrence of mutations in this gene during tumor progression. Project 2, led by Cory Abate-Shen, will analyze the functions of the chromatin remodeling gene, ARID1A, in muscle- invasive bladder cancer, focusing on its role in disease pathogenesis, its effect on treatment response and its molecular mechanisms of action. Project 3, led by Michael Shen, will investigate tumor evolution and drug response in human patient-derived bladder cancer organoids, focusing on genetic determinants of genomic instability, alterations of the epigenome, and the role of heterogeneity in drug sensitivity and resistance. The Molecular Pathology Core (Core A), led by Hikmat Al-Ahmadie, will maintain a biorepository of urothelial cancer tumors, including the tissues used for organoid generation, and will provide histopathological analyses for all three projects. The Bladder Cancer Models Core (Core B), led by Michael Shen will serve as a central hub for the generation and analysis of cancer models for all three projects, including human patient-derived organoid and xenograft models, and GEMMs. The Administrative Core (Core C), led by Cory Abate-Shen, will provide support for bioinformatic and biostatistical analyses and organizational support for Program Project investigators, and will coordinate with the Internal and External Advisory Boards. In summary, this Program Project is led by a highly collaborative team of investigators with diverse but complementary expertise who have substantial track records in cancer research, and are located in close proximity in New York City.