Epi-genetic Programs in Cancer Progression

癌症进展中的表观遗传学项目

• 批准号: 10467022
• 负责人: ROBERT A WEINBERG
• 金额: $ 114.66万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10467022
• 关键词: Behavior; Benign; Biological; Cancerous; Carcinoma; Cell Lineage; Cells; Clinical; Complement; Cytotoxic Chemotherapy; DNA Sequence; Development; Dimensions; Enhancers; Ensure; Epigenetic Process; Epithelial; Exhibits; Gene Proteins; Generations; Genes; Genome; Goals; Growth Factor; Heritability; Human; Inherited; Malignant - descriptor; Malignant Epithelial Cell; Mesenchymal; Molecular; Normal Cell; Oncogenes; Phenotype; Play; Proteins; Research; Research Personnel; Role; Route; Surveys; Therapeutic; Tissues; Tumor Suppressor Genes; Work; behavior influence; cancer cell; cancer genome; cell behavior; cell transformation; cell type; cytokine; genome sequencing; molecular oncology; mutant; neoplastic; non-genetic; novel; programs; promoter; response; trait; transcription factor; tumor; tumor progression; tumorigenic

Project Summary/Abstract: Much of current molecular oncology research is grounded on the paradigm that the behavior of cancer cells and the tumors that they form is dictated by the mutant genomes that these cells have acquired en route to entering into neoplastic/cancerous states. Implicit in this work is the notion that non-genetic mechanisms (that are not directly influenced by DNA sequence) – notably changes organized by non-genetic (i.e., epigenetic) regulatory circuits operating within a cancer cell – play a secondary role in dictating its behavior. In fact, the majority of cancer cell traits may actually be governed by non-genetic regulatory programs that operate in a relatively stable fashion to ensure that many of these traits are transmitted heritably from normal cells-of-origin through multiple cancer cell generations during the course of multi-step tumor development. In addition, activation within carcinoma cells of the cell-biologic program termed the epithelial-mesenchymal transition (EMT) creates a second dimension of cancer cell behavior that is not dictated by the cells' DNA sequences, acting by converting relatively benign carcinoma cells to malignant derivatives. These two non- genetic regulatory mechanisms exert profound effects on the malignant progression of cancer cells and their responsiveness to various forms of therapy. However, relatively little is known about how these non- genetically determined traits of cancer cells are acquired and disrupted during tumor formation. Super-enhancers (SEs) represent large aggregations of transcription factors (TFs) associated with a relatively small number (several hundred) of gene promoters in both normal cells and cancer cells. These SEs are responsible for orchestrating the differentiation programs of a variety of normal cell types that enables them to become tissue-specialized cell types. The proposed research examines the disruptive effects of specific oncogene-encoded proteins (and/or loss of tumor suppressor gene proteins) on the spectrum of SEs within experimentally transformed human cells from a variety of normal cell lineages, with the goal of understanding which SEs survive disruption and continue to influence the behavior of resulting tumorigenic cells (with respect to their responsiveness to therapy and their malignant traits), and which are altered, resulting in the acquisition of novel cancer cell traits. As a complement to these analyses will be an examination of the SEs associated with the EMT programs activated in various types of transformed cells, these being activated either through the induced expression of EMT-inducing TFs or the exposure of transformed cells to known EMT-inducing growth factors and cytokines. By surveying SEs in normal cell types and their neoplastic derivatives, the proposed work will generate an experimental platform that will enable many researchers to finally elucidate at the molecular level why and how various distinct subtypes of human carcinomas naturally exhibit an array of key biological traits or do so in response to imposed cytotoxic therapies.

项目摘要/摘要： 当前的许多分子肿瘤研究都基于癌细胞行为的范例 它们形成的肿瘤由突变基因组决定，即这些细胞在 进入肿瘤/癌状态。这项工作中隐含的是一种非遗传机制（即 不受DNA序列的直接影响） - 特别是通过非遗传组织组织的变化（即表观遗传学） 在癌细胞内运行的调节回路 - 在决定其行为方面起次要作用。 实际上，大多数癌细胞特征实际上可能受到非遗传调节计划的管辖， 以相对稳定的方式进行操作，以确保许多此类特征是从正常的 在多步肿瘤发育过程中，原生气素通过多个癌细胞世代化。在 此外，在细胞生物学程序的癌细胞中的激活称为上皮 - 间质 过渡（EMT）创造了癌细胞行为的第二维，而不是细胞的DNA决定 序列，通过将相对良性癌细胞转化为恶性衍生物而作用。这两个非 - 遗传调节机制对癌细胞的恶性进展产生了深远的影响 对各种形式的治疗的反应。但是，关于这些非 - 在肿瘤形成期间获得并破坏了癌细胞的遗传确定特征。 超级增强剂（SES）代表与相对相关的转录因子（TF）的大量聚集 正常细胞和癌细胞中的少数基因启动子（数百个）。这些SE是 负责策划各种普通细胞类型的差异化程序，使它们能够 成为组织特有的细胞类型。拟议的研究考试特定的特定效果 癌基因编码的蛋白（和/或抑制肿瘤基因蛋白的损失） 实验从多种正常细胞谱系中转化了人类细胞，其目的是理解 SES在破坏中幸存下来并继续影响所产生的肿瘤细胞的行为（尊重 对他们对治疗和恶性特征的反应），并改变了，导致收购 新颖的癌细胞特征。这些分析的完成将是对SES相关的检查 随着EMT程序在各种类型的转化细胞中激活，它们通过 诱导EMT诱导TF的表达或转化的细胞暴露于已知的EMT诱导生长 因素和细胞因子。通过调查正常细胞类型及其肿瘤衍生物的SES，提出了 工作将产生一个实验平台，使许多研究人员能够最终阐明 分子级别为什么以及如何自然暴露着钥匙阵列的各种不同的亚型 生物学特征或响应施加的细胞毒性疗法。