Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant

• DOI: 10.1172/jci74440
• Publication Date: 2015-03-15T22:00:05Z
• Authors: Wies van Roosmalen; Sylvia E. Le Dévédec; Ofra Golani; Marcel Smid; Irina Pulyakhina; Annemieke M. Timm...; Maxime P. Look; Di Zi; Chantal Pont; Marjo de Graauw; Suha Naffar-Abu-A...; Catherine Kirsanova; Gabriella Rustici; Peter A.C. ‘t Hoen; John W.M. Martens; John A. Foekens; Benjamin Geiger; Bob van de Water
• Keywords: 0301 basic medicine; Lung Neoplasms; Bone Neoplasms; Breast Neoplasms; Kaplan-Meier Estimate; Mice; 03 medical and health sciences; SDG 3 - Good Health and Well-being; Cell Movement; Carcinoma, Non-Small-Cell Lung; Cell Adhesion; Animals; Humans; Neoplasm Metastasis; Genetic Association Studies; Focal Adhesions; NF-kappa B; Cell Polarity; Nuclear Proteins; Neoplasm Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; Organ Specificity; Female; EMC MM-03-86-01

Tumor cell migration is a key process for cancer dissemination and metastasis that controlled by signal-mediated cytoskeletal matrix adhesion remodeling. Using phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases adhesome- migration-related proteins to identify affect tumor speed persistence. Thirty candidate altered were validated in live assays. Eight associated metastasis-free survival breast patients, integrin β3–binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), SHC-transforming 1 (SHC1) being the most predictive. Examination modulate indicated SRPK1, splicing factor SRSF 1, relevant outcomes, as it was highly expressed basal cancer. Furthermore, high SRPK1 expression correlated poor disease outcome preferential lungs brain. In 2 independent murine models metastasis, stable shRNA-based knockdown suppressed distant organs, including lung, liver, spleen, inhibited focal reorganization. Our study provides comprehensive information on molecular determinants suggests has potential drug target limiting metastasis.