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.

项目概要/摘要尽管染色质重塑基因 ARID1A 在约 27% 的肌侵袭性膀胱中发生突变癌症（MIBC），其功能后果尚未得到广泛研究。我们建议调查 ARID1A 在膀胱癌发病机制和治疗反应中的作用源自患者的类器官，以及我们生成的基因工程小鼠模型（GEMM）其特点是与该计划项目的同事合作。我们的研究基于重要的初步数据显示 ARID1A 在人膀胱癌细胞中也具有抑癌功能就像小鼠模型一样。特别是，Arid1a 在膀胱癌 GEMM 中的功能丧失加速了肿瘤发生部分是通过 PI-3 激酶信号传导的激活。此外，我们还生成了人类源自患者的膀胱癌类器官，具有人类膀胱癌中出现的 ARID1A 突变，以及研究表明，这些类器官降低了细胞培养物对化疗的反应。最后，使用细胞基于模型，我们已经证明 ARID1A 与 SWI/SNF 染色质复合物的成分相互作用存在于膀胱细胞中，对于这些复合物的形成是必需的，为分子生物学提供了基础 ARID1A 在膀胱癌中的研究。我们现在将研究 ARID1A 缺陷促进膀胱癌发病机制的假设通过改变染色质结构和整体基因表达，从而影响治疗反应。在目标 1 中，我们将研究ARID1A在膀胱肿瘤发生中的功能，及其与其他相关药物的合作表观遗传调节因子和肿瘤抑制因子，通过研究其在 GEMM 中功能丧失的后果，以及基于人类膀胱癌细胞的模型。我们将通过对人类的分析来增强这些研究源自患者的含有 ARID1A 突变的类器官。在目标 2 中，我们将进行联合临床分析研究 ARID1A 失活对化疗反应的影响，并测试是否会产生这种影响通过将化疗与靶向药物或免疫疗法相结合可以改善反应。在目标 3 中，我们将研究 ARID1A 缺陷促进膀胱癌的分子机制，通过执行膀胱癌细胞的生化分析并研究 ARID1A 缺陷对膀胱癌细胞的影响基因表达和染色质结构，这将指导基于机制的翻译工作。整合：我们提出的研究与项目 1 高度互补，项目 1 的重点是表观遗传调节因子 KDM6A 和项目 3，将研究患者来源的膀胱对顺铂的耐药性癌症类器官。此外，该项目的成功将需要核心 A 的投入，它将提供人类肿瘤中分子发现的相关性，并将确定 ARID1A 突变发生的时间膀胱癌； Core B，将协助生成人类类器官和 GEMM；和核心C，这将提供必要的生物信息和统计支持以及程序整合。