The role of calcium-sensitive potassium channels (KCa3.1) in non-small cell lung cancer progression

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The current project aims at deciphering mechanisms by which the calcium-sensitive potassium channel KCa3.1 (encoded by the KCNN4 gene) contributes to the progression of non-small cell lung cancer (NSCLC). We had identified in our previous work the hypomethylation of the KCa3.1 channel promoter and hence overexpression of the channel protein as strong predictors of a poor patient prognosis. Lung cancer, with non-small cell lung carcinoma (NSCLC) being the most frequent subtype, is a leading cause of cancer-related death worldwide with a 5 year survival rate of only ~10 %. Most patients die because of the metastatic spread of the disease. Thus, understanding mechanisms of metastasis is of great pathophysiological significance. The socalled metastatic cascade involves amongst others the adhesion of circulating tumor cells to the endothelium and their subsequent transendothelial migration at the site of metastasis. While the contribution of ion channels to tumor cell apoptosis, proliferation and migration has been well studied, their role in distinct steps of the metastatic cascade is still largely elusive. Here we focus on the calcium-sensitive potassium channel KCa3.1. The channel contributes to the aggressive phenotype of NSCLC cells by controlling their proliferation, apoptosis and migration. However, so far there is only very limited knowledge about the mechanisms by which KCa3.1 channels are driving metastasis and thereby determine patient prognosis. In the present project we will investigate the role of KCa3.1 channels in the extravasation step of the metastatic cascade in NSCLC. KCa3.1 channels are expressed both in NSCLC and in endothelial cells. We hypothesize that KCa3.1 channels are regulating the adhesion of NSCLC cells to the endothelium and their transendothelial migration with KCa3.1 channels from both, NSCLC and endothelial cells, being involved in this process. We will employ a combination of live-cell as well as 3D imaging techniques, atomic force microscopy, microfluidics and a murine model of metastasis. KCa3.1 channel-dependent mechanisms will be determined with a complimentary pharmacological, siRNA and/or knock-out approach. We want to show that KCa3.1 channels (i) regulate the expression and function of the relevant adhesion molecules in a ROS-dependent manner, (ii) ascertain the fine-tuned balance between initial adhesion of NSCLC cells to endothelial cells and their ability to migrate intravascularly to the site of transmigration, and (iii) enable endothelial cells to adopt mechanical properties permissive for transendothelial migration of NSCLC cells. Taken together, our project will provide further evidence that ion channels, long known as important and easily drugable targets in other pathologies such as hypertension, are emerging as a novel class of therapeutic targets in oncology.