EGFR and DNA damage repair signaling networks in glioblastoma

Signal transduction pathways control cellular responses to a wide range of biological stimuli, including growth factors, mitogens, and environmental agents such as temperature, chemical compounds, and radiation. A number of key molecules involved in a variety of signaling pathways are known. However, how cells integrate these signaling pathways to coordinate their responses to multiple simultaneous stimuli, as typically occurs in vivo, is very poorly understood. In my proposal, I will investigate how signaling networks are re-wired in cancer to reveal novel mechanisms of tumorigenic cell survival, focusing on information exchange between DNA damage-repair signaling and epidermal growth factor receptor (EGFR) signaling pathways. The project represents a systems biology approach to study signaling in glioblastoma, an aggressive type of tumors of the central nervous system. They commonly express a constitutive active mutant form of EGFR with renders them resistant to treatment with radiation or DNA-alkylating agents. The study involves a combination of novel high-throughput measurements of time-resolved signaling pathway activation and data-driven mathematical modeling of signaling networks, hopefully leading to new insights into the biological behaviour of normal and malignant cells.