Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant

The Journal of Clinical Investigation
Wies van RoosmalenBob van de Water

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,...Continue Reading

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Datasets Mentioned

BETA
GSE2034
GSE5327
GSE16795

Methods Mentioned

BETA
transfection
nucleotide exchange
bioluminescence imaging
RNA-seq
gene knockdown
fluorescence microscopy
chips

Software Mentioned

PhagoTracker
Tophat
edgeR
ImagePro Plus
WIS
DEXSeq
HTSeq
Cuffdiff
glmLRT
Ensembl

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