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Molecular mechanisms of invadopodium formation

Hideki Yamaguchi^1,3, Mike Lorenz¹, Stephan Kempiak¹, Corina Sarmiento¹, Salvatore Coniglio⁵, Marc Symons^1,2, Jeffrey Segall¹, Robert Eddy¹, Hiroaki Miki^3,6, Tadaomi Takenawa^4,7, and John Condeelis¹

¹ Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461
² Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461
³ Department of Cancer Genomics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
⁴ Department of Biochemistry, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
⁵ Center for Oncology and Cell Biology, North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030
⁶ Precursory Research for Embryonic Science and Technology, Japan Science and Technology Corporation, Tokyo 108-8639, Japan
⁷ Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo 108-8639, Japan

Correspondence to John Condeelis: condeeli{at}aecom.yu.edu

Invadopodia are actin-rich membrane protrusions with a matrix degradation activity formed by invasive cancer cells. We have studied the molecular mechanisms of invadopodium formation in metastatic carcinoma cells. Epidermal growth factor (EGF) receptor kinase inhibitors blocked invadopodium formation in the presence of serum, and EGF stimulation of serum-starved cells induced invadopodium formation. RNA interference and dominant-negative mutant expression analyses revealed that neural WASP (N-WASP), Arp2/3 complex, and their upstream regulators, Nck1, Cdc42, and WIP, are necessary for invadopodium formation. Time-lapse analysis revealed that invadopodia are formed de novo at the cell periphery and their lifetime varies from minutes to several hours. Invadopodia with short lifetimes are motile, whereas long-lived invadopodia tend to be stationary. Interestingly, suppression of cofilin expression by RNA interference inhibited the formation of long-lived invadopodia, resulting in formation of only short-lived invadopodia with less matrix degradation activity. These results indicate that EGF receptor signaling regulates invadopodium formation through the N-WASP–Arp2/3 pathway and cofilin is necessary for the stabilization and maturation of invadopodia.

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