Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant.

J Clin Invest 2015 Apr 16;125(4):1648-64. Epub 2015 Mar 16.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI74440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396474PMC
April 2015
39 Reads

Publication Analysis

Top Keywords

cell migration
24
breast cancer
24
tumor cell
20
cancer metastasis
8
cancer
7
breast
7
migration
7
cell
7
metastasis
6
tumor
6
srpk1
5
srsf protein
4
kinase srsf
4
factor kinase
4
splicing factor
4
migration indicated
4
indicated srpk1
4
srpk1 encoding
4
encoding splicing
4
protein kinase
4

References

(Supplied by CrossRef)

Zaidel-Bar et al.
J Cell Sci. 2010

Geiger et al.
Cold Spring Harb Perspect Biol. 2011

Rijken et al.
J Cell Sci. 1991

Zhang et al.
Mol Cell Biochem. 2011

Di Stefano et al.
Am J Cancer Res. 2011

Similar Publications