Elucidating the stress response regulatory networks that enable malignancy

阐明导致恶性肿瘤的应激反应调节网络

• 批准号: 8734351
• 负责人: Marc Mendillo
• 金额: $ 11.5万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-13 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734351
• 关键词: Adhesions; Antineoplastic Agents; Binding; Biochemistry; Biological Assay; Cancer cell line; Cataloging; Catalogs; Cell Proliferation; Cells; Cessation of life; Clinical; Collaborations; Colon Carcinoma; Computer Simulation; Data; Dependence; Diving; Drug resistance; Energy Metabolism; Epigenetic Process; Gene Expression; Genes; Growth; HSP 90 inhibition; Health; Heat shock proteins; Heat-Shock Response; Homeostasis; Human; Human Cell Line; Institutes; Investigation; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Mediator of activation protein; Mentors; Methods; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenes; Oncogenic; Patients; Phosphotransferases; Post-Translational Protein Processing; Protein Biosynthesis; Proteins; Regulatory Pathway; Reporter Genes; Resected; Resistance; Resources; Role; Signal Transduction; Signal Transduction Pathway; Stress; Technology; Testing; Therapeutic; Training; Tumor Suppressor Proteins; Work; base; biological adaptation to stress; cancer cell; cancer diagnosis; cancer therapy; carcinogenesis; career; heat-shock factor 1; malignant breast neoplasm; malignant phenotype; pre-clinical; programs; response; stressor; tumor

DESCRIPTION (provided by applicant): In previous work we demonstrated that Heat Shock Factor 1 (HSF1), the master transcriptional regulator of the heat-shock response, is a powerful enabler of carcinogenesis. My previous studies establish that HSF1 operates in cancer in ways that are fundamentally distinct from the heat-shock response. In multiple cancers, the HSF1 cancer program is activated and is strongly associated with metastasis and death. The molecular mechanisms responsible for the distinct HSF1 activation state that enables highly malignant cancers remain enigmatic. To define these mechanisms, I will pursue the following aims during the remaining years of mentored training and as I start my independent career: (I) Define the key signal transduction pathways that activate HSF1 in cancer. HSF1 is activated in cancers of diverse origin. How HSF1 is activated in cancer is largely unknown. To define these mechanisms, I will employ a systematic approach using state-of-the-art technologies. I will integrate these data to define the signaling mediators used by the different oncogenic, environmental and endogenous stressors that activate HSF1. (II) Determine how HSF1 produces its distinct transcriptional response in cancer. The transcriptional program HSF1 coordinates in cancer is distinct from that in response to heat-shock. The molecular mechanism responsible for the differences in HSF1 gene occupancy in cancer vs. heat-shock is unknown. I will use mass spectrometry, biochemistry and other methods to determine the molecular basis for this distinct transcriptional response. (III) Determine how HSF1 activation contributes to the poor clinical response.The mechanisms underlying this phenomenon have immense relevance to cancer diagnosis and treatment. One possibility is that HSF1 enables a more malignant phenotype. A second, and non-mutually exclusive possibility is that HSF1 potentiates the emergence of drug resistance. I will use both an in silico approach, based on recently released, publically available data and an experimental approach, based on access to a unique clinical resource through a collaboration. Understanding the regulatory hub of the HSF1 network and how its activation enables a particularly aggressive type of malignancy is of immense clinical importance.

描述（由申请人提供）：在先前的工作中，我们证明了热冲击因子1（HSF1）是热震反应的主要转录调节剂，是致癌作用的强大推动因素。我以前的研究表明，HSF1在癌症中以与热震反应不同的方式进行癌症。在多种癌症中，HSF1癌症计划被激活，并且与转移和死亡密切相关。导致高度恶性癌的独特HSF1激活状态的分子机制仍然神秘。为了定义这些机制，我将在剩余的指导培训的剩余几年中追求以下目标，并且在开始我的独立职业时：（i）定义激活癌症中HSF1的关键信号转导途径。 HSF1在各种起源的癌症中被激活。 HSF1在癌症中的激活方式在很大程度上未知。为了定义这些机制，我将使用最先进的技术采用系统的方法。我将整合这些数据，以定义激活HSF1的不同致癌，环境和内源性应激源使用的信号传导介质。 （ii）确定HSF1如何在癌症中产生其独特的转录反应。癌症中HSF1坐标的转录程序与热震反应不同。导致癌症中HSF1基因占用率差异与热震差异的分子机制尚不清楚。我将使用质谱，生物化学和其他方法来确定这种独特的转录反应的分子基础。 （iii）确定HSF1激活如何导致临床反应不良。该现象与癌症诊断和治疗相关的机制。一种可能性是HSF1实现更恶性的表型。第二个且非缺乏的可能性是HSF1增强了耐药性的出现。我将基于最近发布的公开可用数据和实验方法，基于通过协作访问唯一的临床资源的基础，同时使用一种In In In inico方法。了解HSF1网络的监管中心以及其激活如何使特殊的恶性肿瘤类型具有极大的临床重要性。