Dynamic focal adhesions
Metastasis of cancer cells from the primary tumor site correlates with poor disease outcomes. Tumor cell migration is a complex process that involves remodeling of the cell matrix and reorganization of adhesions to permit interaction with nearby cells and connective tissue. As migratory phenotypes are indicative of metastatic potential, the factors that mediate this process have potential as therapeutic drug targets and prognostic biomarkers. Wies van Roosmalen, Sylvia E. Le Dévédec, and colleagues at Leiden University used a phagokinetic assay to screen over a thousand genes encoding kinases/phosphatases and adhesome- and migration-related proteins and their effect on the migratory human non–small cell lung carcinoma cell line H1299. This screen identified 30 genes that altered migratory phenotypes, and eight of these were associated with metastasis-free survival in patients with breast cancer. In contrast, expression of the gene encoding the kinase SRPK1 in the same cohort of patients associated with increased lung and brain metastasis and poor prognosis. In murine breast cancer models, reduction of SRPK1 suppressed metastasis. This study identifies multiple factors involved in tumor cell migration and suggests that SRPK1 should be further explored as a drug target for limiting metastasis. The accompanying movie shows the effect of targeting different genes on focal adhesion dynamics, which are essential for cell migration. Control and siGFP-treated H1299 cells are migratory and exhibit active focal adhesion remodeling at the leading edge of the cell. Knockdown of either SRPK1 or MAPK2 inhibits cell migration, and focal adhesions are stabilized in siSRPK1- and siMAPK2-treated cells. Knockdown of IKBKE alters migration and depolarizes focal adhesion remodeling.
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Citation Information: J Clin Invest. 2015;125(4):1648-1664. https://doi.org/10.1172/JCI74440.
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 (
Authors
Wies van Roosmalen, Sylvia E. Le Dévédec, Ofra Golani, Marcel Smid, Irina Pulyakhina, Annemieke M. Timmermans, Maxime P. Look, Di Zi, Chantal Pont, Marjo de Graauw, Suha Naffar-Abu-Amara, Catherine Kirsanova, Gabriella Rustici, Peter A.C. ‘t Hoen, John W.M. Martens, John A. Foekens, Benjamin Geiger, Bob van de Water
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