Adressing the molecular basis of tumor thermotherapy

热疗已经被古希腊人使用，是其他文化中对抗各种疾病的传统医学的一部分。在现代医学中，热疗主要用于肿瘤学，通常与放射或化疗相结合。尽管在世界各地的许多研究中都取得了明显的成功，但热疗并不是一种标准的治疗方法，部分原因是肿瘤热疗的分子基础仍然是个谜，而且还没有确定可以预测热疗结果的分子信号。我们项目的目标是了解肿瘤热疗的分子机制细节，并识别可以预测治疗结果的生物标记物。这项工作是基于我们最近的发现，即体温的细微变化控制着一组蛋白激酶(CLK)的活性，导致选择性剪接和基因表达的全球变化。我们现在发现，众所周知的肿瘤抑制因子PP2A磷酸酶的活性对生理相关温度范围的变化有强烈的反应，即在35°C到40°C之间。PP2A活性在更高的温度下增加，这也是热疗所用的温度范围。值得注意的是，我们发现这种磷酸酶活性的增加导致肿瘤抑制基因P53的表达增加，而癌基因Myc的表达减少。由于P53和Myc是肿瘤发生中最重要的参与者，这些数据表明较高的温度与肿瘤抑制有关，而较低的温度与致癌环境有关。本提案的目标1和2旨在详细阐述体温控制P53和Myc表达的分子机制及其细胞类型特异性。该提案的核心部分是使用下一代测序来分析大量的肿瘤，这些肿瘤经过热疗治疗，治疗结果已知。我们将把这些肿瘤的基因组和转录特征与它们对热疗的敏感性联系起来，重点放在PP2A、P53和Myc上，但也要以公正的方式进行。这将允许一种个性化的医学方法，因为它将使我们能够预测单个肿瘤是否可以用热疗治疗。我们结合了一个在体温控制基因表达方面具有强大背景的实验小组的专业知识，以及一个长期专注于热疗的临床小组的专业知识，为一个有可能在基础科学和临床应用方面取得突破性发现的项目创造一个独特的环境。

Thermotherapy has already been used by the ancient Greeks and is part of the traditional medicine of other cultures to fight a variety of diseases. In modern medicine, thermotherapy is used mainly in oncology, often in combination with radiation or chemotherapy. Despite clear success in many studies worldwide, thermotherapy is not a standard treatment, in part because the molecular basis of tumor thermotherapy remains enigmatic and molecular signatures that could predict the outcome of thermotherapy have not been identified. The goal of our project is to understand molecular-mechanistic details of tumor thermotherapy and the identification of biomarkers that can predict treatment outcome. The work is based on our recent finding that subtle changes in body temperature control the activity of a family of kinases (CLKs) leading to global changes in alternative splicing and gene expression. We now show that the activity of the PP2A phosphatase, a well-known tumor suppressor, strongly reacts to changes in the physiologically relevant temperature range, i.e. between 35°C and 40°C. PP2A activity is increased at higher temperature, which is the temperature range also used for thermotherapy. Notably, we find that this increase in phosphatase activity leads to increased expression of the tumor suppressor p53 and decreased expression of the oncogene Myc. As p53 and Myc are amongst the most important players in oncogenesis, these data point to a general correlation of higher temperature with tumor suppression and lower temperature with a pro-oncogenic environment. Aims 1 and 2 of the present proposal are designed to address the molecular mechanism of body temperature controlled p53 and Myc expression and its cell type specificity in detail. A central part of the proposal is then to use next generation sequencing to analyze a large collection of tumors that were treated with thermotherapy with known outcome of the treatment. We will correlate genomic and transcriptomic signatures of these tumors with their susceptibility to thermotherapy, with a focus on PP2A, p53 and Myc, but also in an unbiased manner. This will allow a personalized medicine approach, as it will enable us to predict whether individual tumors can be treated with thermotherapy. We combine expertise of an experimental group with strong background in body temperature-controlled gene expression and a clinical group with longstanding focus on thermotherapy to create a unique environment for a project that has the potential for break-through discoveries in basic science and clinical application.