Epigenomic Mapping in Human Tumor Stem Cells

人类肿瘤干细胞的表观基因组图谱

• 批准号: 8513784
• 负责人: Tan A. Ince
• 金额: $ 57.04万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-21 至 2015-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513784
• 关键词: Affect; Biological Markers; Biological Models; Cells; Coupled; DNA Methylation; Diagnosis; Early Diagnosis; Epigenetic Process; Gene Expression Regulation; Generations; Genomics; Goals; Human; Knowledge; Lead; Light; Malignant Neoplasms; Maps; Molecular Profiling; Monitor; Multipotent Stem Cells; Natural regeneration; Normal Cell; Phenotype; Pluripotent Stem Cells; RNA library; Sorting - Cell Movement; Source; Stem cells; Testing; Translating; Translational Research; Tumor Stem Cells; Tumorigenicity; Untranslated RNA; bisulfite; chromatin immunoprecipitation; chromatin modification; clinically relevant; design; epigenome; epigenomics; genome-wide; histone modification; insight; neoplastic cell; novel therapeutic intervention; outcome forecast; research study; self renewing cell; tumor

The concept of a tumor stem cell, a self-renewing cell capable of regenerating the tumor, has shed light on the persistence of human cancers and offers a new focus for translational research. Our goal is to understand the epigenetic mechanisms that distinguish the tumor stem cell from other cells of the tumor and from other normal, self-renewing cells. Epigenetic mechanisms, such as chromatin modifications, DNA methylation and small noncoding RNAs are stable, long-term (typically heritable) changes in the transcriptional potential of a cell that are independent of changes in the underlying genomic sequence. The epigenetic state of a cell serves to define cell identity and the limits of that cell¿s potential fates. Thus, knowledge of the epigenetic state of cells may identify signature for both tumor stem cell identity and potential. The epigenetic states of histone modifications, DNA methylation and small noncoding RNAs will be mapped using chromatin immunoprecipitation, bisulfite conversion and generation of RNA libraries coupled with genome-wide sequencing. For insight on tumor stem cells, we will take advantage of a previously developed model system that provides a consistent source of cells with tumor stem cell ability. Proposed experiments will examine the differences between a panel of cells, each sorted to enrich for the subpopulation with tumor stem cell ability. For comparisons, non-tumor stem cells will be isolated from the same source and the differences between tumor stem cells and pluripotent and multipotent stem cells will be examined. Additional experiments will be designed to perturb the epigenome of cells and directly test how the epigenetic state of the cell-of-origin affects subsequent tumor phenotype. The knowledge generated could lead to substantial new insights, including the identification of putative markers for early diagnosis, prognosis or monitoring of tumor therapies. Understanding the differences between tumor stem cells and other self-renewing cells could lead to more specific therapies that were also less toxic to normal cells. Manipulating the epigenomic state and examining the results on tumorigenicity would provide direct insight on how these signatures translate into clinically relevant phenotypes.

肿瘤干细胞的概念，一种能够再生肿瘤的自我更新细胞， 揭示了人类癌症的持久性，并为翻译提供了新的焦点。 research.我们的目标是了解区分肿瘤干细胞的表观遗传机制 细胞从肿瘤的其他细胞和其他正常的自我更新细胞。后生 机制，如染色质修饰，DNA甲基化和小的非编码RNA， 细胞转录潜能的稳定、长期（通常是可遗传的）变化， 独立于潜在基因组序列的变化。细胞的表观遗传状态 用来定义细胞的身份和细胞潜在命运的限制。所以，知识 细胞的表观遗传状态可以识别肿瘤干细胞身份和潜能的标记。 组蛋白修饰、DNA甲基化和小分子非编码区的表观遗传状态 RNA将使用染色质免疫沉淀，亚硫酸氢盐转化和生成 RNA文库与全基因组测序相结合。为了深入了解肿瘤干细胞，我们将 利用以前开发的模型系统，该系统提供了一致的 具有肿瘤干细胞能力的细胞。拟议的实验将检查之间的差异 一组细胞，每一个细胞被分选以富集具有肿瘤干细胞能力的亚群。为 比较，非肿瘤干细胞将从相同的来源和差异分离 肿瘤干细胞与多能和多能干细胞之间的关系将被检查。 额外的实验将被设计来扰乱细胞的表观基因组，并直接测试如何 原始细胞的表观遗传状态影响随后的肿瘤表型。 所产生的知识可能会带来大量新的见解，包括 鉴定用于肿瘤治疗的早期诊断、预后或监测的推定标志物。 了解肿瘤干细胞和其他自我更新细胞之间的差异， 从而导致对正常细胞毒性更小的更特异的疗法。操纵 表观基因组状态和检查致瘤性的结果将提供直接的见解， 这些特征如何转化为临床相关的表型。

项目成果

Normal cell-type epigenetics and breast cancer classification: a case study of cell mixture-adjusted analysis of DNA methylation data from tumors.

• DOI: 10.4137/cin.s13980
• 发表时间: 2014
• 期刊: Cancer informatics
• 影响因子: 2
• 作者: Houseman EA;Ince TA
• 通讯作者: Ince TA

Heat shock factor 1 induces cancer stem cell phenotype in breast cancer cell lines.

• DOI: 10.1007/s10549-015-3521-1
• 发表时间: 2015-08
• 期刊: Breast cancer research and treatment
• 影响因子: 3.8
• 作者: Wang B;Lee CW;Witt A;Thakkar A;Ince TA
• 通讯作者: Ince TA

Vitamin D and androgen receptor-targeted therapy for triple-negative breast cancer.

• DOI: 10.1007/s10549-016-3807-y
• 发表时间: 2016-05
• 期刊: Breast cancer research and treatment
• 影响因子: 3.8
• 作者: Thakkar A;Wang B;Picon-Ruiz M;Buchwald P;Ince TA
• 通讯作者: Ince TA