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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/文摘