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（例如代谢进化和蛋白质毒性应激）抗衡 通常会阻碍细胞的存活和增殖。医疗干预对 肿瘤细胞存活。适应这些压力对于癌症的生存和增殖至关重要。这 提案在热休克因子1（HSF1）上，并了解如何在癌症中招募HSF1来支持 肿瘤发生。 HSF1是热冲击响应的主要转录调节器，这是一个强大的 驱动伴侣蛋白表达的细胞保护反应。我们最近表明取消了 共同OPT HSF1用于有效的生长，而HSF1的激活与临床不良结局密切相关。 此外，我们已经表明，癌症中的HSF1转录网络与HSF1计划不同 在热量冲击中，涉及许多非热冲击基因，支持HSF1外热的丰富生物学作用 震惊。对HSF1癌症网络的调节及其在癌症生物学中的作用更完整的视图是 需要。 客观/假设： HSF1激活的两个不同但相关的状态似乎是由热应力驱动的（热量） 休克），但也是由高细胞增殖速率（癌症）的压力驱动的。调节 因此，两个不同状态中的HSF1必须不同 - 通过不同的信号通路和不同的蛋白质 监管机构。此外，HSF1癌症网络控制着潜在的适应性反应 在帮助肿瘤细胞适应靶向治疗和发展耐药性方面的重要作用。 具体目的： 目的1：测试HSF1相互作用组在热休克和癌症和to的预测 表征这些HSF1伴侣蛋白对HSF1在癌症中的活性的影响。目标2：测试 HSF1和HSP90（主要伴侣HSF1调节）的预测对于能力很重要 癌细胞发展靶向治疗的抗性。 研究设计： 我将使用一定定义的癌症线和基于亲和力净化的方法 识别癌症和热冲击中的HSF1相互作用组，并将严格验证已识别的候选人 每个州的监管机构。我将探索HSF1和它调节的主要伴侣HSP90是否可以修改 使用黑色素瘤细胞系系统对BRAF V600E的靶向治疗的抗性的出现， 工程耐药线和高复杂性DNA条形码库，使我们能够评估更改 克隆动力学。 癌症相关性： 识别允许细胞承受并适应挑战的细胞系统 恶性状态对于理解癌症的发展和进化至关重要。 通过支持这些适应的机制，可以提供广泛适用的抗癌策略。