Modeling bladder cancer pathogenesis and tumor evolution

膀胱癌发病机制和肿瘤进化建模

• 批准号: 10218075
• 负责人: Cory Abate-Shen
• 金额: $ 171.9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-11 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218075
• 关键词: ARID1A gene; Abate; Academic Medical Centers; Achievement; Affect; Area; Automobile Driving; Basic Science; Bioinformatics; Biological; Biological Process; Biometry; Bladder; Bladder Tissue; Cancer Model; Cessation of life; Cisplatin; Clinical; Clinical Research; Clonal Evolution; DNA Sequence Alteration; Data Analyses; Disease; Disease Pathway; Disease Progression; Disease model; Drug resistance; Epigenetic Process; Event; Evolution; Experimental Models; Generations; Genes; Genetic Determinism; Genetically Engineered Mouse; Genomic Instability; Genomics; Health; Heterogeneity; Histologic; Human; Impairment; Investigation; Logistics; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Memorial Sloan-Kettering Cancer Center; Metastatic to; Methods; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Mutation; New York City; Oncogenes; Organoids; Pathogenesis; Patients; Pharmaceutical Preparations; Records; Reproducibility; Research; Research Personnel; Resistance; Role; Technology; Tissues; Toxin; United States; Urothelium; Xenograft Model; anticancer research; base; biobank; chemotherapy; chromatin remodeling; clinical investigation; data hub; data integration; disease mechanisms study; drug sensitivity; epigenome; experience; genomic data; genomic platform; histone demethylase; improved; in vivo; innovation; insight; member; molecular pathology; mouse model; multidisciplinary; muscle invasive bladder cancer; novel; novel therapeutic intervention; patient derived xenograft model; programs; response; single-cell RNA sequencing; stem cell biology; treatment response; tumor; tumor heterogeneity; tumor progression

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.

项目概要/摘要： 这个新的计划项目将调查发病机制的分子机制， 膀胱癌我们的目标是：（i）研究从非肌肉侵入性到侵入性的克隆进化， 转移性疾病，并阐明每个进化阶段的分子驱动因素;（ii） 研究其机制 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;（iii） 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;和（iv）产生新的人类患者来源的和基因工程的 小鼠模型（GEMM）研究疾病的发病机制，并进行共同临床研究。实现 为了实现这些目标，我们在哥伦比亚大学组建了一支高水平的跨学科团队 医疗中心（Cory Abate-Shen，Michael Shen，James McKiernan，Tian Zheng）和纪念斯隆 凯特林癌症中心（大卫B。Solit、Hikmat Al-Ahmadie、巴里泰勒），在以下方面具有互补专长： 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 小鼠癌症模型（CAS，MS），共同临床和临床研究（DBS，JM，CAS，JM，MS）。 我们将开展三个相互关联的项目，这些项目由三个核心支持。项目1，由大卫领导 Solit将试图确定组蛋白去甲基化酶KDM 6A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由Cory Abate-Shen领导，将分析肌肉中染色质重塑基因ARID 1A的功能- 浸润性膀胱癌，重点是其在疾病发病机制中的作用，其对治疗反应的影响及其 分子作用机制。由Michael Shen领导的项目3将研究肿瘤演变和药物治疗， 人类患者来源的膀胱癌类器官的反应，重点是基因组的遗传决定因素 不稳定性，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。的 由Hikmat Al-Ahmadie领导的分子病理学核心（核心A）将维持一个尿路上皮细胞的生物储存库， 癌症肿瘤，包括用于类器官生成的组织，并将提供组织病理学分析 这三个项目。由Michael Shen领导的膀胱癌模型核心（Core 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 类器官和异种移植模型以及GEMM。由Cory Abate-Shen领导的行政核心（核心C）将 为生物信息学和生物统计学分析提供支持，并为计划项目提供组织支持 调查员，并将与内部和外部咨询委员会协调。综上所述，本方案 该项目由一个高度协作的调查团队领导，他们具有多样化但互补的专业知识， 在癌症研究方面有大量的跟踪记录，并且位于纽约市附近。