title: Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant.
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.
authors.forename: Wies
authors.initials: W
authors.lastname: van Roosmalen
authors.forename: Sylvia E
authors.initials: SE
authors.lastname: Le Dévédec
authors.forename: Ofra
authors.initials: O
authors.lastname: Golani
authors.forename: Marcel
authors.initials: M
authors.lastname: Smid
authors.forename: Irina
authors.initials: I
authors.lastname: Pulyakhina
authors.forename: Annemieke M
authors.initials: AM
authors.lastname: Timmermans
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.forename: Di
authors.initials: D
authors.lastname: Zi
authors.forename: Chantal
authors.initials: C
authors.lastname: Pont
authors.forename: Marjo
authors.initials: M
authors.lastname: de Graauw
authors.forename: Suha
authors.initials: S
authors.lastname: Naffar-Abu-Amara
authors.forename: Catherine
authors.initials: C
authors.lastname: Kirsanova
authors.forename: Gabriella
authors.initials: G
authors.lastname: Rustici
authors.forename: Peter A C 't
authors.initials: PA
authors.lastname: Hoen
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Benjamin
authors.initials: B
authors.lastname: Geiger
authors.forename: Bob
authors.initials: B
authors.lastname: van de Water
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement / Q000235:genetics; D016764:Cell Polarity; D005260:Female; D022001:Focal Adhesions / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology; D009928:Organ Specificity; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C403295:ITGB3BP protein, human; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C087728:SRPK1 protein, human; C490215:Srpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases