1. Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant.
- Author
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van Roosmalen W, Le Dévédec SE, Golani O, Smid M, Pulyakhina I, Timmermans AM, Look MP, Zi D, Pont C, de Graauw M, Naffar-Abu-Amara S, Kirsanova C, Rustici G, Hoen PA, Martens JW, Foekens JA, Geiger B, and van de Water B
- Subjects
- Animals, Bone Neoplasms secondary, Carcinoma, Non-Small-Cell Lung pathology, Cell Adhesion, Cell Movement genetics, Cell Polarity, Female, Focal Adhesions physiology, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Humans, Kaplan-Meier Estimate, Lung Neoplasms pathology, Lung Neoplasms secondary, Mice, NF-kappa B metabolism, Neoplasm Proteins genetics, Nuclear Proteins physiology, Organ Specificity, Prognosis, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases genetics, RNA Interference, RNA, Small Interfering genetics, Breast Neoplasms genetics, Neoplasm Metastasis genetics, Neoplasm Proteins physiology, Protein Serine-Threonine Kinases physiology
- Abstract
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.
- Published
- 2015
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