Elucidating the stress response regulatory networks that enable malignancy

描述(申请人提供)：在以前的工作中，我们证明了热休克因子1(HSF1)，热休克反应的主要转录调节因子，是一种强大的致癌促进剂。我之前的研究证实，HSF1在癌症中的运作方式与热休克反应根本不同。在多种癌症中，HSF1癌症程序被激活，并与转移和死亡密切相关。导致高度恶性癌症的独特HSF1激活状态的分子机制仍然是个谜。为了确定这些机制，我将在剩下的几年指导培训期间和开始我的独立职业生涯时追求以下目标：(I)确定在癌症中激活HSF1的关键信号转导途径。HSF1在不同来源的癌症中被激活。HSF1是如何在癌症中被激活的在很大程度上是未知的。为了定义这些机制，我将使用一种使用最先进技术的系统方法。我将整合这些数据，以确定激活HSF1的不同致癌、环境和内源性应激源使用的信号媒介。(Ii)确定HSF1如何在癌症中产生其独特的转录反应。HSF1转录程序在癌症中的坐标不同于对热休克的反应。HSF1基因在癌症和热休克中的占有率差异的分子机制尚不清楚。我将使用质谱学、生物化学和其他方法来确定这种独特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。这种现象背后的机制与癌症诊断和治疗有很大的相关性。一种可能性是HSF1导致了更恶性的表型。第二种，也是非互斥的可能性是，HSF1加强了耐药性的出现。我将同时使用基于最近发布的公开可用数据的计算机方法和基于通过合作获得独特临床资源的实验方法。了解HSF1网络的调控中心以及它的激活如何使一种特别侵袭性的恶性肿瘤成为可能，具有巨大的临床重要性。

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.