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A more recent version of this article appeared on November 1, 2007
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Submitted on February 21, 2007
Revised on August 29, 2007
Accepted on August 31, 2007
*Department of Cell Biology, Lerner Research Institute, and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, The Cleveland Clinic, Cleveland, OH 44195; Randall Division of Cell and Molecular Biophysics, King’s College London, Guy’s Campus, London SE1 1UL, United Kingdom
Monitoring Editor: Yu-li Wang
Recurrence of carcinomas due to cells that migrate away from the primary tumor is a major problem in cancer treatment. Immunohistochemical analyses of human carcinomas have consistently correlated up-regulation of the actin-bundling protein fascin with a clinically aggressive phenotype and poor prognosis. To understand the functional and mechanistic contributions of fascin, we undertook inducible shRNA knockdown of fascin in human colon carcinoma cells derived from an aggressive primary tumor. Fascin-depletion led to decreased numbers of filopodia and altered morphology of cell protrusions, decreased Rac-dependent migration on laminin, decreased turnover of focal adhesions and, in vivo, decreased xenograft tumor development and metastasis. cDNA rescue of fascin shRNA-knockdown cells with wild-type GFP-fascin or fascins mutated at the PKC phosphorylation site revealed that both the actin-bundling and active PKC-binding activities of fascin are required for the organization of filopodial protrusions, Rac-dependent migration, and tumor metastasis. Thus, fascin contributes to carcinoma migration and metastasis through dual pathways that impact on multiple subcellular structures needed for cell migration.
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