Invadopodia Are Required for Cancer Cell Extravasation and Are a Therapeutic Target for Metastasis

Hon S. Leong, Amy E. Robertson, Konstantin Stoletov, Sean J. Leith, Curtis A. Chin, Andrew E. Chien, M. Nicole Hague, Amber Ablack, Katia Carmine-Simmen, Victor A. McPherson, Carl O. Postenka, Eva A. Turley, Sara A. Courtneidge, Ann F. Chambers, John D. Lewis

Research output: Contribution to journalArticle

156 Scopus citations

Abstract

Tumor cell extravasation is a key step during cancer metastasis, yet the precise mechanisms that regulate this dynamic process are unclear. We utilized a high-resolution time-lapse intravital imaging approach to visualize the dynamics of cancer cell extravasation invivo. During intravascular migration, cancer cells form protrusive structures identified as invadopodia by their enrichment of MT1-MMP, cortactin, Tks4, and importantly Tks5, which localizes exclusively toinvadopodia. Cancer cells extend invadopodia through the endothelium into the extravascular stroma prior to their extravasation at endothelial junctions. Genetic or pharmacological inhibition of invadopodia initiation (cortactin), maturation (Tks5), or function (Tks4) resulted in an abrogation of cancer cell extravasation and metastatic colony formation in an experimental mouse lung metastasis model. This provides direct evidence of a functional role for invadopodia during cancer cell extravasation and distant metastasis and reveals an opportunity for therapeutic intervention in this clinically important process.

Original languageEnglish (US)
Pages (from-to)1558-1570
Number of pages13
JournalCell Reports
Volume8
Issue number5
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Leong, H. S., Robertson, A. E., Stoletov, K., Leith, S. J., Chin, C. A., Chien, A. E., Hague, M. N., Ablack, A., Carmine-Simmen, K., McPherson, V. A., Postenka, C. O., Turley, E. A., Courtneidge, S. A., Chambers, A. F., & Lewis, J. D. (2014). Invadopodia Are Required for Cancer Cell Extravasation and Are a Therapeutic Target for Metastasis. Cell Reports, 8(5), 1558-1570. https://doi.org/10.1016/j.celrep.2014.07.050