Adressing the molecular basis of tumor thermotherapy

点击翻译按钮获取中文摘要

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.