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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：
10218078
负责人：
Cory Abate-Shen
金额：
$ 36.98万
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/10218078
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.

项目总结/摘要尽管染色质重塑基因ARID 1A在约27%的肌层浸润性膀胱癌中发生突变，癌症（MIBC）的功能后果尚未得到广泛研究。我们建议调查 ARID 1A在膀胱癌发病机制和治疗反应中的作用，使用基于细胞的模型，人类患者来源的类器官，以及我们已经生成的基因工程小鼠模型（GEMM），在这个项目上与同事合作。我们的研究是基于初步数据显示ARID 1A在人膀胱癌细胞中也具有肿瘤抑制功能如小鼠模型中。特别是，膀胱癌GEMM中Arid 1a的功能丧失加速了肿瘤发生，部分通过激活PI-3激酶信号传导。此外，我们还创造了人类具有如人膀胱癌中发生的ARID 1A突变的患者来源的膀胱癌类器官，和已经表明这些类器官在细胞培养中对化疗的反应降低。最后，使用Cell- 基于模型，我们已经表明ARID 1A与SWI/SNF染色质复合物的组分相互作用在膀胱细胞中，是形成这些复合物所必需的，为分子生物学提供了基础。 ARID 1A在膀胱癌背景下的研究我们现在将研究ARID 1A缺乏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。目标1：将研究ARID 1A在膀胱肿瘤发生中的功能，以及它与其他相关基因的合作。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，以及在基于人膀胱癌细胞的模型中。我们将通过对人类的分析来加强这些研究。携带ARID 1A突变的患者源性类器官。在目标2中，我们将进行联合临床分析，研究ARID 1A失活对化疗反应的后果，并测试这种结果是否可以通过将化疗与靶向药物或免疫疗法相结合来改善反应。在目标3中，我们将研究ARID 1A缺陷促进膀胱癌的分子机制，膀胱癌细胞中的生物化学分析，并研究ARID 1A缺乏对膀胱癌细胞的影响。基因表达和染色质结构，这将指导机制为基础的翻译工作。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KDM 6A和项目3，该项目将研究患者来源的膀胱癌对顺铂的耐药性。癌症类器官此外，该项目的成功将需要核心A的投入，核心A将提供人类肿瘤分子发现的相关性，并将定义ARID 1A突变出现的时间在膀胱癌中;核心B，其将有助于人类类器官和GEMM的产生;以及核心C，这将提供必要的生物信息学和统计支持，以及程序集成。