Fascin in filopodial formation and as a target for cancer treatment

Tumor metastasis is the main cause of death of cancer patients. Tumor cell migration and invasion are critical steps in the process of tumor metastasis. For cell migration to proceed, actin cytoskeleton must be reorganized by forming polymers and bundles to affect the dynamic changes of cell shapes. Individual actin filaments are flexible and elongation of individual filaments per se is insufficient for membrane protrusion which is necessary for cell migration. Bundling of actin filaments provides rigidity to actin filaments for protrusion against the compressive force from the plasma membrane. Fascin is the primary actin-bundling protein in filopodia, and is required to maximally cross-link the actin filaments into straight, compact, and rigid bundles. Elevated levels of fascin have been found in metastatic tumors and are correlated with clinically aggressive phenotypes, poor prognosis, and short survival. The objective of this thesis is to understand the role of fascin in filopodial formation and to develop fascin inhibitors as therapeutics for treating and preventing tumor metastasis. Systematic mutagenesis studies on 100 mutants of fascin locate two major actin-binding sites on fascin. Mutations in any one of the actin-binding sites impair the cellular function of fascin in filopodial formation. To identify potential fascin inhibitors, we have developed a sensitive high-throughput screening method and have identified small-molecule inhibitors that decrease the actin-bundling activity of fascin. We have also shown that several of these inhibitors could inhibit tumor cell migration, invasion, and metastasis. We hope further optimization and development of these fascin inhibitors will provide potential therapeutic agents targeting tumor metastasis.