Vivo-Morpholinos: Same oligos, from cultures to critters -


A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions
Robert Kraft, Allon Kahn, José L. Medina-Franco, Mikayla L. Orlowski, Cayla Baynes, Fabian López-Vallejo, Kobus Barnard, Gerald M. Maggiora, Linda L. Restifo


The actin-bundling protein fascin is a key mediator of tumor invasion and metastasis and its activity drives filopodia formation, cell-shape changes and cell migration. Small-molecule inhibitors of fascin block tumor metastasis in animal models. Conversely, fascin deficiency might underlie the pathogenesis of some developmental brain disorders. To identify fascin-pathway modulators we devised a cell-based assay for fascin function and used it in a bidirectional drug screen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arbors manifest the ‘filagree’ phenotype. Taking a repurposing approach, we screened a library of 1040 known compounds, many of them FDA-approved drugs, for filagree modifiers. Based on scaffold distribution, molecular-fingerprint similarities, and chemical-space distribution, this library has high structural diversity, supporting its utility as a screening tool. We identified 34 fascin-pathway blockers (with potential anti-metastasis activity) and 48 fascin-pathway enhancers (with potential cognitive-enhancer activity). The structural diversity of the active compounds suggests multiple molecular targets. Comparisons of active and inactive compounds provided preliminary structure-activity relationship information. The screen also revealed diverse neurotoxic effects of other drugs, notably the ‘beads-on-a-string’ defect, which is induced solely by statins. Statin-induced neurotoxicity is enhanced by fascin deficiency. In summary, we provide evidence that primary neuron culture using a genetic model organism can be valuable for early-stage drug discovery and developmental neurotoxicity testing. Furthermore, we propose that, given an appropriate assay for target-pathway function, bidirectional screening for brain-development disorders and invasive cancers represents an efficient, multipurpose strategy for drug discovery.



    The project was funded by awards to L.L.R. from the National Institutes of Health [grant number NS055774], to L.L.R. and G.M.M. from the Center for Insect Science (University of Arizona), and to J.L.M.-F. from the State of Florida and the Menopause & Women’s Health Research Center (Port St Lucie, FL). C.B. was funded by NIGMS (Minority Access to Research Careers).


    G.M.M. was previously employed by Upjohn and Pharmacia.


    L.L.R. conceived and developed the experimental concepts and directed the project; L.L.R. and R.K. designed experiments; R.K., A.K., M.L.O. and C.B. performed laboratory experiments; R.K., K.B., G.M.M., J.M.-F., F.L.-V., M.L.O., C.B. and L.L.R. contributed data analysis; and L.L.R., R.K., K.B., G.M.M., F.L.-V. and J.M.-F. prepared and edited the manuscript and figures.


    Supplementary material for this article is available at

  • Received January 12, 2012.
  • Accepted July 31, 2012.

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