Relevance of Abnormal KCNN1 Expression and Osmotic Hypersensitivity in Ewing Sarcoma.

Ewing sarcoma (EwS) is a rare and highly malignant bone tumor occurring mainly in childhood and adolescence. Physiologically, the bone is a central hub for Ca homeostasis, which is severely disturbed by osteolytic processes in EwS. Therefore, we aimed to investigate how ion transport proteins involved in Ca homeostasis affect EwS pathophysiology. We characterized the expression of 22 candidate genes of Ca-permeable or Ca-regulated ion channels in three EwS cell lines and found the Ca-activated K channel K2.1 () to be exceptionally highly expressed. We revealed that expression is directly regulated by the disease-driving oncoprotein EWSR1-FL1. Due to its consistent overexpression in EwS, mRNA could be a prognostic marker in EwS. In a large cohort of EwS patients, however, mRNA quantity does not correlate with clinical parameters. Several functional studies including patch clamp electrophysiology revealed no evidence for K2.1 function in EwS cells. Thus, elevated expression is not translated to K2.1 channel activity in EwS cells. However, we found that the low K conductance of EwS cells renders them susceptible to hypoosmotic solutions. The absence of a relevant K conductance in EwS thereby provides an opportunity for hypoosmotic therapy that can be exploited during tumor surgery.