Epi-genetic Programs in Cancer Progression

项目概要/摘要： 目前的大部分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突变的基因组决定的，这些基因组是这些细胞在去 进入肿瘤/癌症状态。这项工作隐含的概念是，非遗传机制（即 不直接受DNA序列的影响）-特别是由非遗传（即，表观遗传学） 在癌细胞内运作的调节回路在决定其行为方面起次要作用。 事实上，大多数癌细胞的特征实际上可能是由非遗传调节程序控制的， 以一种相对稳定的方式运作，以确保这些特征中的许多是从正常的 在多步骤肿瘤发展过程中，通过多个癌细胞代的起源细胞。在 此外，癌细胞内称为上皮-间充质细胞的细胞生物学程序的激活， 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衍生物起作用。这两个非- 遗传调节机制对癌细胞的恶性进展及其 对各种形式治疗的反应。然而，人们对这些非- 在肿瘤形成过程中获得并破坏癌细胞的遗传决定的特征。 超级增强子（SE）代表与相对转录因子相关的转录因子（TF）的大聚集体。 在正常细胞和癌细胞中存在少量（几百个）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 成为组织特异性细胞类型。拟议的研究审查了具体的破坏性影响， 癌基因编码蛋白（和/或肿瘤抑制基因蛋白的缺失） 实验性地从各种正常细胞谱系中转化人类细胞，目的是了解 哪些SE在破坏后存活下来并继续影响所产生的致瘤细胞的行为（相对于 他们对治疗的反应和他们的恶性特征），并改变，导致获得 新的癌细胞特征。作为对这些分析的补充，将对与这些分析相关的SE进行检查。 随着EMT程序在各种类型的转化细胞中被激活，这些被激活的细胞或者通过 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 因子和细胞因子。通过调查正常细胞类型及其肿瘤衍生物中的SE， 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 在分子水平上，为什么以及如何不同的人类癌亚型自然地表现出一系列关键的 生物学特性或响应于强加的细胞毒性疗法而这样做。

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.