Core B: Bladder Cancer Models Core

核心 B：膀胱癌模型核心

基本信息

批准号：
10218083
负责人：
MICHAEL M. SHEN
金额：
$ 20.17万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/10218083
关键词：
3-Dimensional ARID1A gene Address Adenoviruses Alleles Biopsy Bladder Bladder Neoplasm Bladder Urothelium Cancer Model Cell Culture Techniques Cisplatin Clinical Clinical Research Clinical Trials Clonal Evolution Collaborations Communities Complement Consent DNA Sequence Alteration Development Disease Disease Progression Enterobacteria phage P1 Cre recombinase Epigenetic Process Evolution Female Foundations Fresh Tissue Gene Deletion Gene Silencing Gene Targeting Generations Genes Genetically Engineered Mouse Goals Heterogeneity Human Human Characteristics In Vitro Individual Injections Investigation Malignant Neoplasms Malignant neoplasm of urinary bladder Methodology Methods Minority Modeling Molecular Molecular Analysis Mus Mutate Mutation Nucleotide Excision Repair Organoids Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Property Publishing Research Personnel Resources Role Scientific Advances and Accomplishments Series Structure Tamoxifen Ultrasonography Urothelium Woman Work Xenograft procedure anticancer research base biobank cancer cell cancer genomics cancer subtypes cell type clinical investigation clinically relevant co-clinical trial ethnic diversity gender diversity genomic profiles high risk human disease human model implantation in vivo in vivo Model information model innovation interest intravesical loss of function male molecular phenotype mouse model muscle invasive bladder cancer novel novel strategies novel therapeutics patient derived xenograft model patient population programs response targeted exome sequencing tumor tumor heterogeneity tumorigenesis

项目摘要

Project Summary/Abstract Our team has developed novel approaches for the generation of bladder cancer models based on human patient-derived bladder organoids and xenografts, as well as genetically-engineered mouse models (GEMMs). In particular, we have developed an innovative methodology for three-dimensional culture of organoids that recapitulate the histopathological and molecular properties of their corresponding parental tumors, and have mutational profiles characteristic of human bladder cancer. In addition, we have pioneered the development of GEMMs of muscle-invasive bladder cancer (MIBC), and have demonstrated their utility for co-clinical investigations. Together, these resources provide the foundation for the generation and analysis of a range of in vitro and in vivo models of urothelial cancer, which will serve the needs of this Program Project as well as the broader community of bladder cancer researchers. The Bladder Cancer Models Core will support the scientific objectives of our Program Project by generating human and mouse bladder cancer models that will be vital for all three Projects. The Core is structured around two specific aims: In Aim 1, we will establish a biobank of patient-derived bladder cancer organoid lines, including from patients with rare bladder cancer subtypes and genomic alterations of particular interest to the Program Project, and from women and minority patients. In collaboration with Core A, we will perform histopathological and molecular analyses to assess the similarity of the organoids to their corresponding parental tumors, and will use targeted exome sequencing to categorize their mutational profiles. Our goal is to generate a biobank of organoid lines that is representative of the full spectrum of bladder cancer as well as of a diverse patient population. These organoid lines will be utilized by all three Projects, but will be particularly important for Project 3, which will investigate tumor heterogeneity and clonal evolution in patient- derived organoids. In Aim 2, we will generate and characterize a series of GEMMs of bladder cancer, including those of particular relevance for the Program Project, namely Kdm6a, Arid1a, and Kmt2d, which encode epigenetic regulators that are frequently mutated in human bladder cancer, and Ercc2, a nucleotide excision repair pathway gene that is associated with cisplatin response. Using conditional alleles that have been obtained for each of these genes, we will generate GEMMs based on their loss-of-function alone or in combination with Trp53flox/flox; Ptenflox/flox mice, which represents a well-characterized GEMMs of MIBC. Together with Core A, we will perform histopathological and molecular analyses to assess the relationship of these GEMMs to human bladder cancer. These GEMMs will be important for Projects 1 and 2, which will investigate the functions of epigenetic regulators in bladder cancer, and for Project 3, to complement studies in human organoids. Finally, our work will be of considerable value beyond this Program Project by providing clinically-relevant models for the broader community that will facilitate development of new treatments.

项目概要/摘要我们的团队开发了基于膀胱癌模型生成的新方法人类患者膀胱类器官和异种移植物，以及基因工程小鼠模型（GEMM）。特别是，我们开发了一种创新的三维文化方法概括其相应亲本的组织病理学和分子特性的类器官肿瘤，并具有人类膀胱癌的突变特征。此外，我们还开创了肌层浸润性膀胱癌（MIBC）的 GEMM 的开发，并已证明其在治疗中的效用联合临床研究。这些资源共同为生成和分析一系列尿路上皮癌的体外和体内模型，这将满足该计划项目的需求以及更广泛的膀胱癌研究人员群体。膀胱癌模型核心将通过以下方式支持我们计划项目的科学目标：生成对所有三个项目都至关重要的人类和小鼠膀胱癌模型。核心是围绕两个具体目标构建：在目标 1 中，我们将建立患者源性膀胱癌生物库类器官系，包括来自罕见膀胱癌亚型和特定基因组改变的患者以及妇女和少数族裔患者对该计划项目的兴趣。与 Core A 合作，我们将进行组织病理学和分子分析，以评估类器官与其自身的相似性相应的亲本肿瘤，并将使用靶向外显子组测序对其突变谱进行分类。我们的目标是建立一个代表膀胱癌全谱系的类器官生物库以及不同的患者群体。这些类器官品系将被所有三个项目使用，但将对于项目 3 尤为重要，该项目将研究患者的肿瘤异质性和克隆进化衍生的类器官。在目标 2 中，我们将生成并表征一系列膀胱癌的 GEMM，包括那些与计划项目特别相关的，即 Kdm6a、Arid1a 和 Kmt2d，它们编码在人类膀胱癌中经常突变的表观遗传调节因子，以及 Ercc2（一种核苷酸切除）与顺铂反应相关的修复途径基因。使用已经确定的条件等位基因对于这些基因中的每一个获得的基因，我们将根据其单独或单独的功能丧失来生成 GEMM 与 Trp53flox/flox 组合； Ptenflox/flox 小鼠，代表了 MIBC 的良好表征的 GEMM。我们将与 Core A 一起进行组织病理学和分子分析，以评估以下因素之间的关系：这些 GEMM 可以治疗人类膀胱癌。这些 GEMM 对于项目 1 和 2 非常重要，这将研究膀胱癌中表观遗传调节因子的功能，并为项目 3 补充以下研究人类类器官。最后，我们的工作将具有超出本计划项目的相当大的价值，通过提供为更广泛的社区提供临床相关模型，将促进新疗法的开发。