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Epigenomic Reprogramming in Patient Derived Models of Colorectal Cancer

患者衍生的结直肠癌模型中的表观基因组重编程

基本信息

批准号：
10241490
负责人：
SHIAOWEN David HSU
金额：
$ 51.69万
依托单位：
DUKE UNIVERSITY
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：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241490
关键词：
Affect Antineoplastic Agents Biopsy CD34 gene Cancer Model Cells Chemoresistance Clinical Clustered Regularly Interspaced Short Palindromic Repeats Colorectal Cancer DNA Sequence Alteration Data Development Drug resistance Drug usage Engineering Environment Epigenetic Process Evolution Fluorouracil Future Genome Growth Guide RNA Heterogeneity Histone Deacetylase Inhibitor Human Immune Immune Evasion Immune system Immunity Immunocompetent Immunodeficient Mouse Libraries Malignant Neoplasms Measures Modeling Molecular Neoplasm Metastasis Organoids Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Play Population Pre-Clinical Model Research Personnel Role Sampling Serial Passage Site Specimen Technology Testing Text Time Xenograft procedure base bone cancer cell clinical application colon cancer patients cytotoxic design drug discovery epigenetic regulation epigenome epigenomics humanized mouse insight irinotecan metastatic colorectal multidisciplinary neoplastic cell novel oxaliplatin patient derived xenograft model pre-clinical pressure reconstitution response screening small molecule standard of care targeted agent tool transcriptome translational study transplant model tumor tumor growth tumor microenvironment tumor xenograft whole genome

项目摘要

SUMMARY Patient derived models of cancer (PDMC) are supposed to recapitulate clinical human cancer more faithfully, and these preclinical models are being increasingly used for drug discovery and mechanistic studies. However, there have been no systematic studies that compare the PDMCs to understand whether different PDMC growth environments can cause distinct phenotypic and molecular changes to patient- derived cancer cells carrying the same genetic mutations This proposal aims to test an overarching hypothesis that patient-derived cancer cells can undergo distinct epigenetic reprogramming in response to the different PDMC environments, which impact tumor phenotypes such as heterogeneity, chemoresistance, metastasis, and immune adaptation. By assembling a multidisciplinary team consisting of clinicians, geneticists, and engineers, this project will systematically profile the epigenomes of three PDMC colorectal cancer (CRC) models: organoid, patient- derived xenograft (PDX), and humanized immunoproficient PDX. The evolution of the tumor cell epigenetic landscape in PDMC (and vs. original patient tumors) and in response to therapy will be investigated. Whether P matched primary and metastatic CRCs from the same patient remain epigenetically distinct or converge will also be tested. A novel precision CRISPR-based epigenomic editing screening technology will then identify specific epigenetic drivers that contribute to PDMC tumor growth and chemoresistance. If successful, this comprehensive study will systematically characterize the differences between these PDMCs, which will be informative for future basic and translational studies. Furthermore, this study will provide insights into epigenetic regulation of CRC chemoresistance, metastasis, and immune evasion. These insights are important thanks to emerging evidence suggesting that genetic mutation alone cannot account for all phenotypic changes across PDMCs. In contrast to small molecule epigenetic modifiers which affect the genome globally, screening using the novel CRISPR-based epigenomic editing technology will be able to identify specific epigenomic drivers for the first time.

摘要患者衍生的癌症模型(Pdmc)被认为更能概括人类的临床癌症。这些临床前模型正越来越多地被用于药物发现和机制学习。然而，目前还没有系统的研究来比较PDMC以了解是否不同的PDMC生长环境可导致患者不同的表型和分子变化- 携带相同基因突变的衍生癌细胞这项提议旨在测试一个压倒一切的假设，即患者来源的癌细胞可以经历不同的影响肿瘤的不同PDMC环境下的表观遗传重编程表型，如异质性、化疗耐药、转移和免疫适应。通过组建一个由临床医生、遗传学家和工程师组成的多学科团队，该项目将系统地描述三种PDMC结直肠癌(CRC)模型的表观基因组：器质性、患者- 衍生异种移植(PDX)和人源化免疫熟练的PDX。肿瘤细胞的进化 PDMC(和原始患者肿瘤)的表观遗传景观和对治疗的反应将是调查过了。同一患者的原发癌和转移性癌是否P匹配仍然存在表观遗传上的截然不同或融合也将受到测试。一种新的基于CRISPR的表观基因组编辑筛查技术将确定导致PDMC肿瘤生长的特定表观遗传驱动因素以及抗药性。如果成功，这项全面的研究将系统地描述它们之间的差异 PDMC，这将为今后的基础和翻译研究提供信息。此外，这项研究将提供对结直肠癌化疗耐药、转移和免疫逃避的表观遗传调控的见解。这些见解是重要的，这要归功于新出现的证据表明，仅靠基因突变不能解释整个PDMC的所有表型变化。与小分子表观遗传修饰剂相比使用基于CRISPR的新的表观基因组编辑技术进行筛选将能够首次识别特定的表观基因组驱动因素。