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.

概括患者衍生的癌症模型（PDMC）应该更多地概括临床人类癌忠实的，这些临床前模型越来越多地用于药物发现和机理研究。但是，没有系统的研究可以比较PDMC以了解是否了解是否不同的PDMC生长环境可能会导致患者的不同表型和分子变化带有相同基因突变的衍生癌细胞该提案旨在检验一个总体假设，即患者衍生的癌细胞可以经历不同响应不同的PDMC环境的表观遗传重编程，这会影响肿瘤异质性，化学抗性，转移和免疫适应性等表型。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，该项目将系统地介绍了三种PDMC结直肠癌（CRC）模型的表观构想：类器官，患者 - 衍生的异种移植物（PDX）和人源化免疫专有PDX。肿瘤细胞的演变 PDMC中的表观遗传景观（以及原始患者肿瘤），对治疗的反应将是调查。 P匹配同一患者的原发性和转移性CRC是否仍然存在表观遗传学上的不同或收敛也将进行测试。一种新颖的基于CRISPR的精密表观基因组编辑然后，筛选技术将确定有助于PDMC肿瘤生长的特定表观遗传驱动因素和化学抗性。如果成功，这项全面的研究将系统地表征它们之间的差异 PDMC，这对于将来的基础和翻译研究提供了信息。此外，这项研究将提供有关CRC化学抗性，转移和免疫逃避的表观遗传调节的见解。这些见解非常重要，这要归功于新兴的证据表明仅基因突变不能解释PDMC之间的所有表型变化。与小分子表观遗传修饰剂相反它在全球影响基因组，使用基于CRISPR的新型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器。