Epi-genetic Programs in Cancer Progression

项目摘要/摘要： 目前的许多分子肿瘤学研究都是基于这样一种范式，即癌细胞的行为 它们形成的肿瘤是由这些细胞在途中获得的突变基因组决定的 进入肿瘤/癌症状态。这项工作中隐含的概念是非遗传机制(即 不受DNA序列的直接影响)--由非遗传(即表观遗传)组织的显著变化 在癌细胞内运行的调节电路在决定其行为方面起着次要作用。 事实上，大多数癌细胞的特征实际上可能是由非基因调控程序控制的，这些程序 以一种相对稳定的方式运行，以确保这些特征中的许多是从正常遗传来的 在肿瘤的多步骤发展过程中，通过多代癌细胞产生起源细胞。在……里面 此外，癌细胞内激活的细胞生物学程序称为上皮-间充质 过渡(EMT)创造了癌细胞行为的第二个维度，而不是由细胞的DNA决定的 序列，通过将相对良性的癌细胞转化为恶性的衍生品来起作用。这两个非- 基因调控机制对癌细胞及其癌变的恶性进展有着深远的影响 对各种形式的治疗的反应。然而，相对较少的人知道这些非 癌细胞的基因决定特征在肿瘤形成过程中被获得和破坏。 超级增强子(SE)代表转录因子(TF)的大集合，与相对 在正常细胞和癌细胞中都有少量(数百个)基因启动子。这些SE是 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。这项拟议的研究考察了特定的 癌基因编码蛋白(和/或肿瘤抑制基因蛋白丢失) 实验转化了来自各种正常细胞系的人类细胞，目的是了解 哪些SE在破坏中幸存下来并继续影响由此产生的致瘤细胞的行为(恕我直言 与他们对治疗的反应性和他们的恶性特征有关)，并被改变，导致获得 新的癌细胞特征。作为对这些分析的补充，将对相关的SE进行检查 随着EMT程序在各种类型的转化细胞中激活，这些程序可以通过 EMT诱导的TF的诱导表达或转化细胞暴露于已知的EMT诱导生长 因子和细胞因子。通过对正常细胞类型及其肿瘤衍生物中的SE进行调查，建议的 工作将产生一个实验平台，使许多研究人员最终能够在 分子水平为什么以及如何不同的人类癌症亚型自然地表现出一系列关键的 生物学特征或这样做是对强加的细胞毒治疗的反应。

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.