Core B: Bladder Cancer Models Core

核心 B：膀胱癌模型核心

基本信息

批准号：
10475026
负责人：
MICHAEL M. SHEN
金额：
$ 18.52万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475026
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 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 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 minority patient 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 ultrasound

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.

项目摘要/摘要我们的团队开发了基于膀胱癌模型的新方法人类患者衍生的膀胱器官和异种移植物，以及遗传工程的小鼠模型（宝石）。特别是，我们为三维文化开发了一种创新的方法论概括其相应父母的组织病理学和分子特性的器官肿瘤，并具有人类膀胱癌特征的突变特征。此外，我们还开创了肌肉侵入性膀胱癌（MIBC）的发育，并证明了它们的实用性共同研究。这些资源共同为生成和分析的基础尿路上皮癌的体外和体内模型范围，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社区。膀胱癌模型核心将支持我们计划项目的科学目标产生人类和小鼠膀胱癌模型，对于这三个项目至关重要。核心是围绕两个具体的目标结构：在AIM 1中，我们将建立一个由患者来源的膀胱癌的生物库器官线，包括来自罕见膀胱癌亚型的患者以及特定的基因组改变该计划项目以及妇女和少数族裔患者的兴趣。与A Core A合作，我们将进行组织病理学和分子分析以评估器官的相似性相应的亲本肿瘤，并将使用靶向的外显子组测序对其突变谱进行分类。我们的目标是生成一个代表全膀胱癌谱的器官线生物库以及多样化的患者人群。所有三个项目都将使用这些类器官线，但是对于项目3特别重要，该项目将研究患者的肿瘤异质性和克隆进化派生的类器官。在AIM 2中，我们将生成并描述一系列膀胱癌的宝石，包括与程序项目（即KDM6A，ARID1A和KMT2D）特别相关的那些经常在人膀胱癌中突变的表观遗传调节剂和核苷酸切除ERCC2 与顺铂反应相关的修复途径基因。使用有条件等位基因为每个基因获得的每个基因获得，我们将基于它们的功能丧失或在与TRP53Flox/Flox结合； Ptenflox/Flox小鼠，代表MIBC的特征良好的宝石。与核心A一起，我们将进行组织病理学和分子分析以评估这些宝石是人类膀胱癌。这些宝石对于项目1和2将很重要，这将研究表观遗传调节剂在膀胱癌中的功能，以及项目3的功能，以补充研究人体器官。最后，我们的工作将通过提供该计划项目的价值临床上与更广泛社区的临床模型，将有助于开发新的治疗方法。