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Sci. Signal., 26 July 2011
Vol. 4, Issue 183, p. ra49
[DOI: 10.1126/scisignal.2002032]

RESEARCH ARTICLES

A Cell-Based High-Content Screening Assay Reveals Activators and Inhibitors of Cancer Cell Invasion

Manuela Quintavalle1, Leonardo Elia2,3, Jeffrey H. Price1,4, Susanne Heynen-Genel1, and Sara A. Courtneidge1*

1 Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Department of Medicine, Division of Cardiology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
3 MultiMedica-IRCCS, via Gaudenzio Fantoli 16/15, Milan 20138, Italy.
4 Vala Sciences Inc., 11575 Sorrento Valley Road, Suite 204, San Diego, CA 92121, USA.

Abstract: Acquisition of invasive cell behavior underlies tumor progression and metastasis. To further define the molecular mechanisms underlying invasive behavior, we developed a high-throughput screening strategy to quantitate invadopodia, which are actin-rich membrane protrusions of cancer cells that contribute to tissue invasion and matrix remodeling. We tested the LOPAC 1280 collection of pharmacologically active agents in a high-content, image-based assay and identified compounds that inhibited invadopodium formation without overt toxicity, as well as compounds that increased invadopodia number. The chemotherapeutic agent paclitaxel increased both the number of invadopodia and the invasive behavior of various human cancer cell lines, effects that have potential clinical implications for its use before surgical removal of a primary tumor (neoadjuvant therapy) or in patients with chemoresistant tumors. Several compounds that inhibited invasion have been characterized as cyclin-dependent kinase (Cdk) inhibitors, and loss-of-function experiments determined that Cdk5 was the relevant target. We further determined that Cdk5 promoted both invadopodium formation and cancer cell invasion by phosphorylating and thus decreasing the abundance of the actin regulatory protein caldesmon.

* To whom correspondence should be addressed. E-mail: courtneidge{at}sanfordburnham.org

Citation: M. Quintavalle, L. Elia, J. H. Price, S. Heynen-Genel, S. A. Courtneidge, A Cell-Based High-Content Screening Assay Reveals Activators and Inhibitors of Cancer Cell Invasion. Sci. Signal. 4, ra49 (2011).

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