Systems Biology of Lung Cancer - Linking Dynamic Properties of Signaling Networks to Migratory Behavior of Lung Carcinoma Cells in Monolayer Culture
Sofia Depner, Lars Velten, Ruth Merkle, A Mathur, Franziska Matthaeus, Ursula Klingmüller · Pneumologie · 2012
Lung cancer, with its predominant form non-small cell lung cancer (NSCLC), is the leading cause of cancer related-deaths world-wide. The key medical problem in lung cancer is early systemic spread of tumors independent of tumor size. Activating mutations or overexpression of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF) receptor (c-Met) are frequently observed. A major unresolved question is how these receptor systems interact and contribute to early spread in lung cancer. To unravel key regulatory mechanisms and to establish a quantitative link of information processing through signaling networks, target gene induction and lung cancer cell migration, we are employing a selected panel of NSCLC adenocarinoma cell lines with defined EGFR status. In monolayer cultures we are monitoring HGF induced signal transduction and activation kinetics of cMet, Akt and Erk1/2 by quantitative immunoblotting and quantitative mass spectrometry in the presence of various inhibitors. Studies at the molecular level are complemented by studies of cellular decisions in response of HGF such as proliferation, migration and apoptosis at the cell population level. The quantitative data obtained is used to establish detailed mechanistic models of signaling pathways that will be utilized to identify key regulatory mechanisms and predict strategies for targeted intervention.