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c-Src differentially regulates the functions of microtentacles and invadopodia

Oncogene volume 29, pages 6402–6408 (2010)Cite this article

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Abstract

During metastasis, invading cells produce various actin-based membrane protrusions that promote directional migration and proteolysis of extracellular matrix (ECM). Observations of actin staining within thin, tubulin-based microtentacle (McTN) protrusions in suspended MDA-MB-231 tumor cells, prompted an investigation of whether McTNs are structural or functional analogs of invadopodia. We show here that MDA-MB-231 cells are capable of producing invadopodia and McTNs, both of which contain F-actin. Invadopodium formation was enhanced by the expression of a constitutively active c-Src kinase, and repressed by the expression of dominant-negative, catalytically inactive form of c-Src. In contrast, expression of inactive c-Src significantly increased McTN formation. Direct inhibition of c-Src with the SU6656 inhibitor compound also significantly enhanced McTN formation, but suppressed invadopodia, including the appearance of F-actin cores and phospho-cortactin foci, as well as completely blocking focal degradation of ECM. In addition, silencing of Tks5 in Src-transformed fibroblasts blocked invadopodia without affecting McTNs. Genetic modification of c-Src activity that promoted McTN formation augmented capillary retention of circulating tumor cells in vivo and rapid re-attachment of suspended cells in vitro, even though invadopodia were strongly suppressed. These results indicate that McTNs are capable of enhancing tumor cell reattachment, even in the absence of Tks5 and active Src, and define separate cytoskeletal mechanisms and functions for McTNs and invadopodia.

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Abbreviations

ECM:

extracellular matrix

McTN:

microtentacle

F-actin:

filamentous actin

PDGFR:

platelet derived growth factor receptor

References

  • Balzer EM, Whipple RA, Cho EH, Matrone MA, Martin SS . (2010). Antimitotic chemotherapeutics promote adhesive responses in detached and circulating tumor cells. Breast Cancer Res Treat 121: 65–78.

    Article  Google Scholar 

  • Blake RA, Broome MA, Liu X, Wu J, Gishizky M, Sun L et al. (2000). SU6656, a selective src family kinase inhibitor, used to probe growth factor signaling. Mol Cell Biol 20: 9018–9027.

    Article  CAS  Google Scholar 

  • Buccione R, Caldieri G, Ayala I . (2009). Invadopodia: specialized tumor cell structures for the focal degradation of the extracellular matrix. Cancer Metastasis Rev 28: 137–149.

    Article  Google Scholar 

  • Buccione R, Orth JD, McNiven MA . (2004). Foot and mouth: podosomes, invadopodia and circular dorsal ruffles. Nat Rev Mol Cell Biol 5: 647–657.

    Article  CAS  Google Scholar 

  • Chambers AF, Groom AC, MacDonald IC . (2002). Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2: 563–572.

    Article  CAS  Google Scholar 

  • Clark ES, Weaver AM . (2008). A new role for cortactin in invadopodia: regulation of protease secretion. Eur J Cell Biol 87: 581–590.

    Article  CAS  Google Scholar 

  • Frame MC, Fincham VJ, Carragher NO, Wyke JA . (2002). v-Src's hold over actin and cell adhesions. Nat Rev Mol Cell Biol 3: 233–245.

    Article  CAS  Google Scholar 

  • Gupton SL, Gertler FB . (2007). Filopodia: the fingers that do the walking. Sci STKE 2007: re5.

    Article  Google Scholar 

  • Korb T, Schlüter K, Enns A, Spiegel HU, Senninger N, Nicolson GL et al. (2004). Integrity of actin fibers and microtubules influences metastatic tumor cell adhesion. Exp Cell Res 299: 236–247.

    Article  CAS  Google Scholar 

  • Linder S . (2007). The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. Trends Cell Biol 17: 107–117.

    Article  CAS  Google Scholar 

  • Linder S, Aepfelbacher M . (2003). Podosomes: adhesion hot-spots of invasive cells. Trends Cell Biol 13: 376–385.

    Article  CAS  Google Scholar 

  • Machesky LM . (2008). Lamellipodia and filopodia in metastasis and invasion. FEBS Lett 582: 2102–2111.

    Article  CAS  Google Scholar 

  • Mehlen P, Puisieux A . (2006). Metastasis: a question of life or death. Nat Rev Cancer 6: 449–458.

    Article  CAS  Google Scholar 

  • Mendoza M, Khanna C . (2009). Revisiting the seed and soil in cancer metastasis. Int J Biochem Cell Biol 41: 1452–1462.

    Article  CAS  Google Scholar 

  • Miles FL, Pruitt FL, van Golen KL, Cooper CR . (2008). Stepping out of the flow: capillary extravasation in cancer metastasis. Clin Exp Metastasis 25: 305–324.

    Article  CAS  Google Scholar 

  • Mitra SK, Schlaepfer DD . (2006). Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18: 516–523.

    Article  CAS  Google Scholar 

  • Seals DF, Azucena Jr EF, Pass I, Tesfay L, Gordon R, Woodrow M et al. (2005). The adaptor protein Tks5/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cells. Cancer Cell 7: 155–165.

    Article  CAS  Google Scholar 

  • Whipple RA, Balzer EM, Cho EH, Matrone MA, Yoon JR, Martin SS . (2008). Vimentin filaments support extension of tubulin-based microtentacles in detached breast tumor cells. Cancer Res 68: 5678–5688.

    Article  CAS  Google Scholar 

  • Whipple RA, Cheung AM, Martin SS . (2007). Detyrosinated microtubule protrusions in suspended mammary epithelial cells promote reattachment. Exp Cell Res 313: 1326–1336.

    Article  CAS  Google Scholar 

  • Yilmaz M, Christofori G . (2009). EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 28: 15–33.

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by R01-CA124704 grant from the National Cancer Institute, Breast Cancer Idea Award from USA Medical Research and Materiel Command (BC061047) and a Susan G Komen investigator-initiated grant (KG100240). We are very grateful to Darren Seals and Sara Courtneidge for generously providing cell lines and reagents to examine the role of Tks5.

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Authors and Affiliations

  1. Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    E M Balzer, A E Boggs, J Slovic, E H Cho, M A Matrone & S S Martin

  2. Department of Physiology, Marlene and Stewart Greenebaum NCI Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

    E M Balzer, R A Whipple, K Thompson, E H Cho, M A Matrone & S S Martin

  3. Department of Biochemistry, Osaka University Graduate School of Dentistry, Osaka, Japan

    T Yoneda

  4. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, DC, USA

    S C Mueller

Authors
  1. E M Balzer
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  2. R A Whipple
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  3. K Thompson
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  4. A E Boggs
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  5. J Slovic
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  6. E H Cho
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  9. S C Mueller
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Correspondence to S S Martin.

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Balzer, E., Whipple, R., Thompson, K. et al. c-Src differentially regulates the functions of microtentacles and invadopodia. Oncogene 29, 6402–6408 (2010). https://doi.org/10.1038/onc.2010.360

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