Abstract SY02-04: Regulation of invadopodia formation and cancer cell invasion

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Abstract Cell invasion plays a central role in a wide variety of biological phenomena, and is the cause of tumor growth and metastasis. Understanding the biochemical mechanisms that control cell invasion is one of the major goals of our laboratory. Podosomes and invadopodia are specialized cellular structures present in cells with physiological or pathological invasive behaviors. These transient structures are localized at the ventral cell surface, contain an array of different proteins, and facilitate cell-substrate adhesion as well as the local proteolytic activity necessary for extracellular matrix remodeling and subsequent cellular invasion. We have previously shown that the adaptor protein and Src substrate Tks5 is required for both podosome and invadopodia formation, and for tumor growth in vivo. More recently we also defined a role for the Tks5-mediated generation of reactive oxygen species (ROS). We have developed a high content, cell-based high throughput screening assay that allows us to identify inhibitors and activators of invadopodia formation. As a proof of principle, we tested the LOPAC1280 collection of small molecules and found 7 inhibitory compounds and 2 activators. Of the 7 inhibitors, 4 are cyclin-dependent kinase (Cdk) inhibitors. Loss-of-function experiments demonstrated that Cdk5 is the responsible kinase. On the other hand, paclitaxel was one of the two compounds that increased invadopodia formation. We have also used our high content assay to screen a large compound collection as well as an siRNA library targeting the entire kinome. The mechanisms by which Cdk5 and tubulin regulate invadopodia formation, and the nature of the other regulators, are the subjects of our current investigations. Citation Format: Barbara Blouw, Matt Buschman, Pilar Cejudo-Martin, Begoña Diaz, Christine Gould, Danielle Murphy, Manuela Quintavalle, Susanne Heynen, Behrad Azimi, Jeff Price, Sara A. Courtneidge. Regulation of invadopodia formation and cancer cell invasion [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY02-04