Epi-genetic Programs in Cancer Progression

癌症进展中的表观遗传学项目

• 批准号: 10684706
• 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/10684706
• 关键词: Behavior; Benign; Biological; Cancerous; Carcinoma; Cell Lineage; Cells; Clinical; Complement; Cytotoxic Chemotherapy; DNA Sequence; Development; Dimensions; Enhancers; Epigenetic Process; Epithelium; Exhibits; Gene Proteins; Generations; Genes; Genome; Goals; Growth Factor; Heritability; Human; Inherited; Malignant - descriptor; Malignant Epithelial Cell; Mesenchymal; Molecular; Normal Cell; Oncogenes; Organizational Change; 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; transmission process; 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学研究都基于这样的范式：癌细胞的行为 它们形成的肿瘤是由这些细胞在形成过程中获得的突变基因组决定的 这项工作隐含着非遗传机制（即进入肿瘤/癌症状态）的概念。 不受 DNA 序列直接影响）——由非遗传（即表观遗传）组织的显着变化 癌细胞内运行的调节回路在决定其行为方面发挥次要作用。 事实上，大多数癌细胞特征实际上可能受到非基因调控程序的控制，这些程序 以相对稳定的方式运作，以确保其中许多特征是从正常人遗传而来的 在多步肿瘤发展过程中，通过多个癌细胞世代来识别起源细胞。 此外，癌细胞内细胞生物学程序的激活被称为上皮间质细胞 转变（EMT）创造了癌细胞行为的第二个维度，不受细胞 DNA 的支配 序列，通过将相对良性的癌细胞转化为恶性衍生物来发挥作用。 基因调控机制对癌细胞及其恶性进展产生深远影响 然而，对于这些非疗法如何产生反应，人们知之甚少。 癌细胞的遗传决定特征在肿瘤形成过程中获得并被破坏。 超级增强子 (SE) 代表转录因子 (TF) 的大量聚集，与相对 正常细胞和癌细胞中都有少量（数百个）基因启动子。 负责协调各种正常细胞类型的分化程序，使它们能够 成为组织特化的细胞类型。拟议的研究检查了特定细胞的破坏性影响。 SE 谱上的癌基因编码蛋白（和/或肿瘤抑制基因蛋白的丢失） 通过实验转化来自各种正常细胞谱系的人类细胞，目的是了解 哪些SE能够在破坏中幸存下来并继续影响所产生的致瘤细胞的行为（相对于 他们对治疗的反应及其恶性特征），并且这些被改变，导致获得 作为这些分析的补充，将检查相关的 SE。 随着 EMT 程序在各种类型的转化细胞中被激活，这些程序可以通过 诱导 EMT 诱导 TF 的表达或将转化细胞暴露于已知的 EMT 诱导生长 通过调查正常细胞类型及其肿瘤衍生物中的 SE，提出了以下建议： 这项工作将产生一个实验平台，使许多研究人员能够最终阐明 分子水平上人类癌症的各种不同亚型为何以及如何自然地表现出一系列关键特征 生物特征或这样做是为了响应强加的细胞毒性疗法。