title: Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization.
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.
authors.affiliation: Department of Physiology and Biophysics, Cornell University Weill Medical College, New York, New York 10065, USA.
authors.forename: Fang-Ke
authors.initials: FK
authors.lastname: Huang
authors.affiliation: Department of Physiology and Biophysics, Cornell University Weill Medical College, New York, New York 10065, USA.
authors.forename: Shaoqin
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Physiology and Biophysics, Cornell University Weill Medical College, New York, New York 10065, USA.
authors.forename: Bowen
authors.initials: B
authors.lastname: Xing
authors.affiliation: Department of Physiology and Biophysics, Cornell University Weill Medical College, New York, New York 10065, USA.
authors.forename: Jianyun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Physiology and Biophysics, Cornell University Weill Medical College, New York, New York 10065, USA.
authors.forename: Bingqian
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Bordeleau
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Reinhart-King
authors.affiliation: Department of Physiology and Biophysics, Cornell University Weill Medical College, New York, New York 10065, USA.
authors.forename: J Jillian
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Biophysics, Cornell University Weill Medical College, New York, New York 10065, USA.
authors.forename: Xin-Yun
authors.initials: XY
authors.lastname: Huang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002465:Cell Movement / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy*; D011554:Pseudopodia / Q000187:drug effects*
chemical_list: D000199:Actins; D002352:Carrier Proteins; D007191:Indazoles; D008840:Microfilament Proteins; C000606767:N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide; C020324:fascin