TY - JOUR AU - van Roosmalen, Wies AU - Le Dévédec, Sylvia E. AU - Golani, Ofra AU - Smid, Marcel AU - Pulyakhina, Irina AU - Timmermans, Annemieke M. AU - Look, Maxime P. AU - Zi, Di AU - Pont, Chantal AU - de Graauw, Marjo AU - Naffar-Abu-Amara, Suha AU - Kirsanova, Catherine AU - Rustici, Gabriella AU - Hoen, Peter A.C. ‘t AU - Martens, John W.M. AU - Foekens, John A. AU - Geiger, Benjamin AU - van de Water, Bob T1 - Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant PY - 2015/04/01/ AB - Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin β3–binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI74440 VL - 125 IS - 4 UR - https://doi.org/10.1172/JCI74440 SP - 1648 EP - 1664 PB - The American Society for Clinical Investigation ER -