Abstract 4021: A kinome screen identifies SRPK1 to mediate breast cancer metastasis

Abstract

Abstract Tumor cell migration plays key role in cancer cell dissemination and metastasis and is controlled by signaling-mediated cytoskeletal and cell-matrix adhesion remodeling. Using a phagokinetic track (PKT) assay with migratory H1299 cells, we performed a siRNA screen of almost 1,500 genes encoding kinases/phosphatases, adhesome-related and migration-related proteins, with the aim of identifying genes that determine tumor cell migration speed, and persistence. Thirty candidate genes, showing significant effect were validated in live tumor cell migration assays, and eight of those had a significant association with metastasis free survival in breast cancer patients, ITGB3BP, MAP3K8, NEK2, SHC1 and SRPK1 being most significant . Further examination indicated that the expression of SRPK1, the most interesting gene identified in this screen , was highest in basal-like breast cancer and its expression level was correlated with poor disease outcome and preferred metastasis to the lungs and brain. In two independent breast tumor metastasis models, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver and spleen and inhibited focal adhesion reorganization. We provide here a comprehensive information resource on the molecular determinants of tumor cell migration and identify SRPK1 as a potential candidate drug target associated with breast cancer metastasis. Citation Format: Bob van de Water, Wies van Roosmalen, Sylvia Le Devedec, John Meerman, John Foekens, John Martens, Benny Geiger. A kinome screen identifies SRPK1 to mediate breast cancer metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4021. doi:10.1158/1538-7445.AM2014-4021