Project 2: Functions of ARID1A in muscle invasive bladder cancer

项目2：ARID1A在肌层浸润性膀胱癌中的功能

基本信息

批准号：
10475016
负责人：
Cory Abate-Shen
金额：
$ 28.9万
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/10475016
关键词：
1-Phosphatidylinositol 3-Kinase ARID1A gene Affect Biochemical Bioinformatics Biological Bladder Cancer Etiology Cancer Patient Cell Culture Techniques Cell physiology Cells Cessation of life Chromatin Chromatin Remodeling Factor Chromatin Structure Cisplatin Clinical Clinical Research Clinical Trials Collaborations Complex Couples DNA Damage Data Disease Disease Progression Epigenetic Process Evolution Expression Profiling Foundations Future Gene Expression Gene Expression Regulation Generations Genes Genetically Engineered Mouse Genomics Goals Human Immunotherapy In Vitro Investigation Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Modeling Molecular Mutate Mutation Organoids PI3 gene PTEN gene Pathogenesis Patients Pharmaceutical Preparations Pharmacotherapy Resistance Role SWI/SNF Family Complex Series Signal Transduction TP53 gene Testing Therapeutic Intervention Tissues Tumor Suppressor Proteins Tumorigenicity United States Work base cancer cell chemotherapy chromatin remodeling combinatorial design epigenome genome-wide human model immune checkpoint improved in vivo innovation insight loss of function mTOR Signaling Pathway mouse model muscle invasive bladder cancer programs protein complex resistance mutation response success targeted agent transcriptome treatment response tumor tumor growth tumor progression tumorigenesis

项目摘要

Project Summary/Abstract Although the chromatin remodeling gene ARID1A is mutated in ~27% of muscle invasive bladder cancer (MIBC), the functional consequences have not been extensively studied. We propose to investigate the role of ARID1A in bladder cancer pathogenesis and treatment response using cell-based models, human patient-derived organoids, and genetically-engineered mouse models (GEMMs) that we have generated and characterized in collaboration with colleagues on this Program Project. Our studies are based on significant preliminary data showing that ARID1A has tumor suppressor functions in human bladder cancer cells as well as in mouse models. In particular, loss-of-function of Arid1a in a GEMM of bladder cancer accelerates tumorigenesis, in part through activation of PI-3 kinase signaling. Additionally, we have generated human patient-derived bladder cancer organoids that have ARID1A mutations as occur in human bladder cancer, and have shown that these organoids have reduced response to chemotherapy in cell culture. Lastly, using cell- based models, we have shown that ARID1A interacts with components of the SWI/SNF chromatin complexes in bladder cells and is necessary for formation of these complexes, providing a foundation for molecular investigations of ARID1A in bladder cancer contexts. We will now investigate the hypothesis that ARID1A deficiency promotes bladder cancer pathogenesis by altering chromatin structure and global gene expression, thereby affecting treatment response. In Aim 1, we will investigate the functions of ARID1A in bladder tumorigenesis, and its collaboration with other relevant epigenetic regulators and tumor suppressors, by studying the consequences of its loss-of-function in GEMMs, as well as in human bladder cancer cell-based models. We will augment these studies with analyses of human patient-derived organoids that harbor ARID1A mutations. In Aim 2, we will perform co-clinical analyses to investigate the consequences of ARID1A inactivation for response to chemotherapy, and to test whether such response can be improved by combining chemotherapy with targeted agents or immunotherapy. In Aim 3, we will study the molecular mechanisms by which ARID1A deficiency promotes bladder cancer, by performing biochemical analyses in bladder cancer cells and investigating the consequences of ARID1A deficiency for gene expression and chromatin structure, which will guide mechanism-based translational efforts. Integration: Our proposed studies are highly complementary with Project 1, which is focused on the epigenetic regulator KDM6A, and Project 3, which will study resistance to cisplatin in patient-derived bladder cancer organoids. Additionally, the success of this project will require input from Core A, which will provide human tumors for correlation of molecular findings and will define the timing at which ARID1A mutations arise in bladder cancer; Core B, which will assist with the generation of human organoid and GEMMs; and Core C, which will provide essential bioinformatic and statistical support, as well as program integration.

项目摘要/摘要尽管染色质重塑基因ARID1A在〜27％的肌肉浸润性膀胱中突变癌症（MIBC），功能后果尚未得到广泛研究。我们建议调查使用基于细胞的模型，ARID1A在膀胱癌发病机理和治疗反应中的作用，人类我们已经产生的患者衍生的类器官和遗传工程的小鼠模型（GEMM）与该计划项目的同事合作的特征。我们的研究是基于重要的初步数据表明，ARID1A在人膀胱癌细胞中也具有肿瘤抑制器的功能如鼠标模型。特别是，在膀胱癌的宝石中，ARID1A的功能丧失加速肿瘤发生，部分通过激活PI-3激酶信号传导。此外，我们已经产生了人类患者衍生的膀胱癌器官具有ARID1A突变，如人类膀胱癌，并且已经表明，这些器官在细胞培养中对化学疗法的反应减少了。最后，使用细胞 - 基于模型，我们表明ARID1A与SWI/SNF染色质复合物的组件相互作用在膀胱细胞中，对于这些复合物的形成是必要的，为分子提供了基础膀胱癌环境中Arid1a的研究。现在，我们将研究ARID1A缺乏症促进膀胱癌发病机理的假设通过改变染色质结构和全球基因表达，从而影响治疗反应。在AIM 1中，我们将研究ARID1A在膀胱肿瘤发生中的功能，及其与其他相关的合作表观遗传调节剂和肿瘤抑制剂，通过研究其在GEMMS中的功能丧失的后果，以及在人类膀胱癌细胞基于的模型中。我们将通过对人类的分析来增强这些研究具有ARID1A突变的患者衍生的类器官。在AIM 2中，我们将进行共同分析研究ARID1A灭活对化疗的后果，并测试是否存在可以通过将化学疗法与靶向药物或免疫疗法结合使用来改善反应。在AIM 3中，我们将研究通过执行ARID1A缺乏促进膀胱癌的分子机制膀胱癌细胞中的生化分析并研究了ARID1A缺乏症的后果基因表达和染色质结构将指导基于机制的转化工作。整合：我们提出的研究与项目1高度互补，该项目的重点是表观遗传调节剂KDM6A和项目3，该项目将研究患者来源的膀胱中对顺铂的抗性癌器官。此外，该项目的成功将需要核心A的输入，这将提供人类肿瘤用于分子发现的相关性，并将定义出现ARID1A突变的时机在膀胱癌中；核心B，将有助于产生人体器官和宝石；和核心C，这将提供必不可少的生物信息学和统计支持以及计划集成。