Investigating the HSF1 Cancer Network

调查 HSF1 癌症网络

• 批准号: 9173740
• 负责人: Sandro Santagata
• 金额: $ 40.6万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-11 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9173740
• 关键词: Affinity Chromatography; Antineoplastic Agents; BRAF gene; Bar Codes; Biological; Cancer Biology; Cell Line; Cell Proliferation; Cell Survival; Cells; Clinical; DNA; DNA Damage; Defense Mechanisms; Development; Drug resistance; Engineering; Event; Evolution; Fostering; Genes; Goals; Growth; Growth and Development function; Heat-Shock Proteins 90; Heat-Shock Response; Heat-Shock Transcription Factor 2; Human; Hypoxia; Intervention; Knowledge; Libraries; Malignant - descriptor; Malignant Neoplasms; Medical; Melanoma Cell; Metabolic; Mitotic; Modeling; Molecular Chaperones; Normal Cell; Organism; Outcome; Patient-Focused Outcomes; Play; Proteins; Recruitment Activity; Regulation; Research Design; Resistance; Resistance development; Ribosomes; Role; S-Phase Fraction; Shock; Signal Pathway; Signal Transduction; Stress; System; Temperature; Testing; Translations; Vision; Work; Yeasts; anti-cancer therapeutic; base; cancer cell; cancer survival; cancer type; design; heat-shock factor 1; hormone therapy; inhibitor/antagonist; malignant breast neoplasm; malignant state; neoplastic cell; oxidative damage; pressure; programs; response; stem; stressor; targeted treatment; thermal stress; tumor; tumor progression; tumorigenesis

PROJECT SUMMARY/ABSTRACT Background: Cancer cells contend with many obstacles such as metabolic derangements and proteotoxic stress that would normally hamper cell survival and proliferation. Medical interventions impose additional impediments for tumor cell survival. Adaptation to these pressures is essential for cancer survival and proliferation. This proposal is on heat shock factor 1 (HSF1) and understanding how HSF1 is recruited in cancer to support tumorigenesis. HSF1 is the master transcriptional regulator of the heat shock response, a powerful cytoprotective response that drives expression of chaperone proteins. We have recently shown that cancers co-opt HSF1 for efficient growth and that activation of HSF1 is strongly associated with poor clinical outcome. In addition, we have shown that the HSF1 transcriptional network in cancer is distinct from the HSF1 program in heat shock and involves many non-heat shock genes, supporting a rich biological role for HSF1 outside heat shock. A more complete view of the regulation of the HSF1 cancer network and its role in cancer biology is needed. Objective/Hypothesis: There appear to be two distinct but related states of HSF1 activation: one driven by thermal stress (heat shock) but also one driven by the pressure of high rates of cellular proliferation (cancer). The regulation of HSF1 in the two distinct states must therefore be different – via distinct signaling pathways and distinct protein regulators. In addition, the HSF1 cancer network governs such a potent adaptive response that it may play an important role in helping tumor cells adapt to targeted therapeutics and in developing resistance. Specific Aims: Aim 1: To test the prediction that the HSF1 interactome is different in heat shock and in cancer and to characterize the effects of these HSF1 partner proteins on the activity of HSF1 in cancer. Aim 2: To test the prediction that HSF1 and HSP90 (one of the principal chaperones HSF1 regulates) are important for the ability of cancer cells to develop resistance to targeted therapeutics. Study design: I will use a genetically defined panel of cancer lines and affinity purification based approaches to identify the HSF1 interactome in cancer and heat shock and will rigorously validate identified candidate regulators for each state. I will explore if HSF1 and a principal chaperone that it regulates, HSP90, can modify the emergence of resistance to targeted therapeutics for BRAF V600E using melanoma cell lines systems, engineered resistant lines and high complexity DNA bar code libraries that allow us to assess changes in clonal dynamics. Cancer relevance: Identifying the cellular systems that allow cells to withstand and adapt to the challenges of the malignant state is of critical importance for understanding the development and evolution of cancer. Interfering with the mechanisms that support these adaptations may provide a broadly applicable anti-cancer strategy.

项目摘要/摘要 背景资料： 癌细胞与代谢紊乱和蛋白毒性应激等许多障碍作斗争， 通常会阻碍细胞的存活和增殖。医疗干预措施增加了 肿瘤细胞存活。适应这些压力对于癌症的生存和扩散至关重要。这 一项关于热休克因子1（HSF 1）的提案，并了解HSF 1如何在癌症中招募，以支持 肿瘤发生HSF 1是热休克反应的主要转录调节因子，是一个强大的转录调节因子。 细胞保护反应，驱动分子伴侣蛋白的表达。我们最近发现癌症 为了有效生长而选择HSF 1，并且HSF 1的激活与不良临床结果强烈相关。 此外，我们已经表明，在癌症中的HSF 1转录网络是不同于HSF 1程序 HSF 1在热休克中的作用，涉及许多非热休克基因，支持HSF 1在热休克外具有丰富的生物学作用 冲击.对HSF 1癌症网络的调节及其在癌症生物学中的作用的更完整的看法是 needed. 目的/假设： 似乎有两种不同但相关的HSF 1激活状态：一种是由热应力（热 休克），但也有一个由高速率的细胞增殖（癌症）的压力驱动。调控 因此，两种不同状态下的HSF 1一定是不同的--通过不同的信号通路和不同的蛋白质 监管部门此外，HSF 1癌症网络控制着如此强大的适应性反应，它可能在癌症中发挥重要作用。 在帮助肿瘤细胞适应靶向治疗和产生耐药性方面发挥重要作用。 具体目标： 目的1：检验HSF 1相互作用组在热休克和癌症中不同的预测， 表征这些HSF 1伴侣蛋白对癌症中HSF 1活性的影响。目标2：测试 预测HSF 1和HSP 90（HSF 1调节的主要伴侣之一）对于 癌细胞对靶向治疗产生耐药性。 研究设计： 我将使用一组基因定义的癌细胞系和基于亲和纯化的方法， 确定癌症和热休克中的HSF 1相互作用组，并将严格验证已确定的候选物 每个州的监管机构。我将探索HSF 1和它调节的主要分子伴侣HSP 90是否可以改变 使用黑色素瘤细胞系系统对BRAF V600 E的靶向治疗剂产生耐药性， 工程抗性品系和高复杂性DNA条形码文库，使我们能够评估 克隆动态 癌症相关性： 确定允许细胞承受和适应环境挑战的细胞系统 恶性状态对于理解癌症的发展和演变至关重要。干扰 支持这些适应的机制可能提供广泛适用的抗癌策略。