Epigenomic Reprogramming in Patient Derived Models of Colorectal Cancer

总结 病人来源的癌症模型（PDMC）被认为更能概括临床人类癌症 这些临床前模型正越来越多地用于药物发现和机制研究。 问题研究然而，还没有系统的研究比较PDMC，以了解是否 不同的PDMC生长环境可引起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 该提案旨在测试一个总体假设，即患者来源的癌细胞可以经历不同的细胞周期。 表观遗传重编程响应于不同的PDMC环境，其影响肿瘤 表型如异质性、化学抗性、转移和免疫适应。 通过组建由临床医生、遗传学家和工程师组成的多学科团队，该项目将 系统地分析了三种PDMC结直肠癌（CRC）模型的表观基因组：类器官、患者- 衍生的异种移植物（PDX）和人源化免疫活性PDX。肿瘤细胞的演变 PDMC（和与原始患者肿瘤）中的表观遗传景观以及对治疗的反应将是 研究了是否存在同一患者的P匹配的原发性和转移性CRC 表观遗传学上不同或趋同也将被测试。一种新的基于CRISPR的精确表观基因组编辑 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 和耐药性。 如果成功，这项全面的研究将系统地描述这些之间的差异， PDMC，这将是为未来的基础和翻译研究提供信息。此外，本研究将 提供了对CRC化疗耐药性、转移和免疫逃避的表观遗传调控的见解。 这些见解很重要，因为有新的证据表明，单靠基因突变不能 解释了PDMC的所有表型变化。与小分子表观遗传修饰剂相比， 在全球范围内影响基因组，使用基于CRISPR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。

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.