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Epigenetic plasticity in tumor initiation and evolution

肿瘤发生和进化中的表观遗传可塑性

基本信息

批准号：
10441748
负责人：
BRADLEY Evan BERNSTEIN
金额：
$ 23.01万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-21 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10441748
关键词：
Epigenetic plasticity tumor initiation evolution

项目摘要

Project Summary: Gene activity is modulated in different cell types by the way genomic DNA is packaged into chromatin – a process termed ‘epigenetics’. Epigenetic controls are disrupted in nearly all forms of cancer, as well as in many other human diseases. This may occur through mutation of chromatin regulators, environmental exposures that alter chromatin structure, or inappropriate developmental cues. There is enormous enthusiasm for the potential of ‘epigenetic therapies’ to correct epigenetic defects in clinical settings. However, we currently lack coherent models or mechanistic understanding of how epigenetic defects promote tumors, or how they might be modulated in clinical intervention. The proposed project will pursue a novel, unifying model for how epigenetic lesions drive tumor initiation and evolution. We hypothesize that a key function of most epigenetic lesions is to induce plasticity, which allows pre-malignant or malignant cells to stochastically sample alternate gene regulatory programs. Cells that adopt programs that confer fitness (proliferation, tolerance, etc) are selected, and their epigenetic state maintained through cell division, giving rise to a new lineage and, ultimately, to malignant progression. Newly established technologies for profiling, monitoring and modulating epigenetic landscapes, including at single cell level, provide a unique opportunity to test this hypothesis and characterize the underlying mechanisms. We will focus initially on exemplar lesions that drive brain tumor initiation and evolution. The first exemplar is isocitrate dehydrogenase (IDH) gene mutations and associated DNA hyper-methylation, which we hypothesize cause stochastic disruption of chromatin boundaries and insulators, thereby allowing aberrant induction of oncogenes. The second exemplar is stress-induced histone demethylation, which we posit allows cancer stem cells to access primitive developmental programs and evolve drug tolerance. We will deeply characterize these exemplars by leveraging clinical specimens and experimental models, and by further innovating new technologies. We will then explore the extent to which plasticity pertains to other oncogenic lesions and to other diseases with epigenetic etiologies. In summary, the proposed study will deeply investigate mechanisms of epigenetic deregulation and plasticity in tumorigenesis. The research has potential to radically alter current views of epigenetic regulation in human disease, and thus has important biomedical implications.

项目概要：不同细胞类型中的基因活性通过基因组 DNA 包装到染色质中的方式进行调节—— 过程称为“表观遗传学”。表观遗传控制在几乎所有形式的癌症以及在许多其他人类疾病。这可能是由于染色质调节因子、环境因素的突变而发生的。改变染色质结构的暴露或不适当的发育线索。有巨大的对“表观遗传疗法”纠正临床环境中表观遗传缺陷的潜力充满热情。然而，我们目前缺乏对表观遗传缺陷如何产生连贯的模型或机制的理解。促进肿瘤，或如何在临床干预中调节它们。拟议的项目将寻求一种新颖的、统一的模型来解释表观遗传损伤如何驱动肿瘤起始和演化。我们假设大多数表观遗传损伤的关键功能是诱导可塑性，它允许癌变前或恶性细胞随机采样替代基因调控程序。选择采用赋予适应性（增殖、耐受性等）程序的细胞，并选择它们的表观遗传通过细胞分裂维持这种状态，产生新的谱系，并最终导致恶性进展。新建立的用于分析、监测和调节表观遗传景观的技术，包括单细胞水平，提供了一个独特的机会来检验这一假设并表征潜在的机制。我们将首先关注驱动脑肿瘤发生和进化的典型病变。这第一个例子是异柠檬酸脱氢酶 (IDH) 基因突变和相关的 DNA 高甲基化，我们假设这会导致染色质边界和绝缘体的随机破坏，从而允许癌基因的异常诱导。第二个例子是应激诱导的组蛋白去甲基化，我们假设允许癌症干细胞进入原始发育程序并进化出药物耐受性。我们将通过利用临床标本和实验模型来深入描述这些范例，并通过进一步创新新技术。然后我们将探讨可塑性与其他事物的关系程度致癌病变和具有表观遗传病因的其他疾病。总之，拟议的研究将深入研究表观遗传失调的机制和肿瘤发生的可塑性。该研究有可能从根本上改变当前对表观遗传调控的看法人类疾病中，因此具有重要的生物医学意义。