Abstract
One of the key steps during tumour metastasis is tumour cell migration and invasion, which require actin cytoskeletal reorganization. Among the critical actin cytoskeletal protrusion structures are the filopodia, which act like cell sensory organs to communicate with the extracellular microenvironment and participate in fundamental cell functions such as cell adhesion, spreading and migration in the three-dimensional environment. Fascin is the main actin-bundling protein in filopodia. Using high-throughput screening, here we identify and characterize small molecules that inhibit the actin-bundling activity of fascin. Focusing on one such inhibitor, we demonstrate that it specifically blocks filopodial formation, tumour cell migration and invasion in vitro, and metastasis in vivo. Hence, target-specific anti-fascin agents have a therapeutic potential for cancer treatment.
Highlights
One of the key steps during tumour metastasis is tumour cell migration and invasion, which require actin cytoskeletal reorganization
From a systematic mutagenesis study of 100 fascin mutants, we identified at least two major actin-binding sites on fascin, and that each of these actin-binding sites is essential for the filopodial formation in cells[44]
The migrastatin analogues that we have previously investigated belong to a class of chemical compounds with similar core chemical scaffold
Summary
One of the key steps during tumour metastasis is tumour cell migration and invasion, which require actin cytoskeletal reorganization. Using high-throughput screening, here we identify and characterize small molecules that inhibit the actin-bundling activity of fascin Focusing on one such inhibitor, we demonstrate that it blocks filopodial formation, tumour cell migration and invasion in vitro, and metastasis in vivo. Metastasis is comprised of a series of events that a primary tumour spreads from its initial site to secondary tissues/organs[3] This invasionmetastasis cascade includes cell migration/invasion, intravasation, survival in the circulation, arrest in a distant capillary bed and extravasation into and colonization within the organ parenchyma. Filopodia are finger-like plasma membrane protrusions that are formed upon remodelling of the actin cytoskeleton beneath the plasma membrane[13] They can be viewed as a sensory organ of the cells that are used to detect and assimilate signals as well as to explore and move into the surrounding microenvironment[14,15,16]. Fascin has been suggested as a therapeutic target for blocking tumour cell migration, invasion and metastasis[31,32,35,36,37,38,39,40,41,42,43]
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