Investigating the HSF1 Cancer Network

调查 HSF1 癌症网络

• 批准号: 9767105
• 负责人: Sandro Santagata
• 金额: $ 39.38万
• 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/9767105
• 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; Genetic Transcription; Goals; Growth; Growth and Development function; HSF1; Heat-Shock Proteins 90; 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; Regulation; Research Design; Resistance; Resistance development; Ribosomes; Role; S-Phase Fraction; Signal Pathway; Signal Transduction; Stress; System; Temperature; Testing; Translations; Vision; Work; Yeasts; anti-cancer; anti-cancer therapeutic; base; biological adaptation to stress; cancer cell; cancer survival; cancer type; design; drug development; heat-shock factor 1; hormone therapy; inhibitor/antagonist; malignant breast neoplasm; malignant state; neoplastic cell; oxidative damage; pressure; programs; proteotoxicity; recruit; 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： 癌细胞与许多障碍作斗争，如代谢紊乱和蛋白毒性应激 通常会阻碍细胞的存活和增殖。医疗干预增加了其他障碍， 肿瘤细胞存活率。适应这些压力对于癌症的生存和增殖至关重要。这 建议是关于热休克因子1(HSF1)和了解HSF1如何在癌症中招募以支持 肿瘤发生学。HSF1是热休克反应的主要转录调节因子，是一种强大的 推动伴侣蛋白表达的细胞保护反应。我们最近已经证明，癌症 共同选择HSF1以实现高效生长，且HSF1激活与不良的临床结果密切相关。 此外，我们还表明，癌症中的HSF1转录网络不同于HSF1程序 在热休克中，涉及许多非热休克基因，支持热休克外HSF1丰富的生物学作用 令人震惊。对HSF1癌症网络的调控及其在癌症生物学中的作用的更全面的看法是 需要的。 目标/假设： HSF1的激活似乎有两种不同但相关的状态：一种是由热应激(热)驱动的 休克)，但也是由高细胞增殖率(癌症)的压力驱动的。监管 因此，处于两种不同状态的HSF1肯定是不同的--通过不同的信号通路和不同的蛋白质 监管者。此外，HSF1癌症网络控制着如此强大的适应性反应，以至于它可能扮演着 在帮助肿瘤细胞适应靶向治疗和发展耐药性方面发挥重要作用。 具体目标： 目的1：验证HSF1相互作用组在热休克和癌症中不同的预测。 描述这些HSF1伙伴蛋白在癌症中对HSF1活性的影响。目标2：测试 预测HSF1和HSP90(HSF1调节的主要伴侣之一)对能力是重要的 肿瘤细胞对靶向治疗产生抗药性。 研究设计： 我将使用基因定义的癌症株和基于亲和纯化的方法来 确定HSF1在癌症和热休克中的相互作用组，并将严格验证已确定的候选基因 每个州的监管机构。我将探索HSF1及其调节的主要伴侣HSP90是否可以修改 使用黑色素瘤细胞系系统对BRAF V600E靶向治疗出现耐药性， 设计的抗性品系和高复杂性DNA条形码库，使我们能够评估 克隆动力学。 癌症相关性： 识别使细胞能够承受和适应 恶性状态对于了解癌症的发展和演变具有至关重要的作用。干扰 通过支持这些适应的机制，可能提供一种广泛适用的抗癌策略。