Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Invading one step at a time: the role of invadopodia in tumor metastasis

Oncogene volume 33, pages 4193–4202 (2014)Cite this article

Subjects

Abstract

The ability to degrade extracellular matrix is critical for tumor cells to invade and metastasize. Recent studies show that tumor cells use specialized actin-based membrane protrusions termed invadopodia to perform matrix degradation. Invadopodia provide an elegant way for tumor cells to precisely couple focal matrix degradation with directional movement. Here we discuss several key components and regulators of invadopodia that have been uniquely implicated in tumor invasion and metastasis. Furthermore, we discuss existing and new therapeutic opportunities to target invadopodia for anti-metastasis treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Thiery JP . Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2: 442–454.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Murphy DA, Courtneidge SA . The ‘ins’ and ‘outs’ of podosomes and invadopodia: characteristics, formation and function. Nat Rev Mol Cell Biol 2011; 12: 413–426.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Weed SA, Parsons JT . Cortactin: coupling membrane dynamics to cortical actin assembly. Oncogene 2001; 20: 6418–6434.

    CAS  PubMed  Google Scholar 

  5. Okamura H, Resh MD . p80/85 cortactin associates with the Src SH2 domain and colocalizes with v-Src in transformed cells. J Biol Chem 1995; 270: 26613–26618.

    CAS  PubMed  Google Scholar 

  6. Huang C, Liu J, Haudenschild CC, Zhan X . The role of tyrosine phosphorylation of cortactin in the locomotion of endothelial cells. J Biol Chem 1998; 273: 25770–25776.

    CAS  PubMed  Google Scholar 

  7. Bowden ET, Barth M, Thomas D, Glazer RI, Mueller SC . An invasion-related complex of cortactin, paxillin and PKCmu associates with invadopodia at sites of extracellular matrix degradation. Oncogene 1999; 18: 4440–4449.

    CAS  PubMed  Google Scholar 

  8. Artym VV, Zhang Y, Seillier-Moiseiwitsch F, Yamada KM, Mueller SC . Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer Res 2006; 66: 3034–3043.

    CAS  PubMed  Google Scholar 

  9. Bowden ET, Onikoyi E, Slack R, Myoui A, Yoneda T, Yamada KM et al. Co-localization of cortactin and phosphotyrosine identifies active invadopodia in human breast cancer cells. Exp Cell Res 2006; 312: 1240–1253.

    CAS  PubMed  Google Scholar 

  10. Yamaguchi H, Lorenz M, Kempiak S, Sarmiento C, Coniglio S, Symons M et al. Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin. J Cell Biol 2005; 168: 441–452.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Oser M, Yamaguchi H, Mader CC, Bravo-Cordero JJ, Arias M, Chen X et al. Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. J Cell Biol 2009; 186: 571–587.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Patel AS, Schechter GL, Wasilenko WJ, Somers KD . Overexpression of EMS1/cortactin in NIH3T3 fibroblasts causes increased cell motility and invasion in vitro. Oncogene 1998; 16: 3227–3232.

    CAS  PubMed  Google Scholar 

  13. Li Y, Tondravi M, Liu J, Smith E, Haudenschild CC, Kaczmarek M et al. Cortactin potentiates bone metastasis of breast cancer cells. Cancer Res 2001; 61: 6906–6911.

    CAS  PubMed  Google Scholar 

  14. Chuma M, Sakamoto M, Yasuda J, Fujii G, Nakanishi K, Tsuchiya A et al. Overexpression of cortactin is involved in motility and metastasis of hepatocellular carcinoma. J Hepatol 2004; 41: 629–636.

    CAS  PubMed  Google Scholar 

  15. Schuuring E . The involvement of the chromosome 11q13 region in human malignancies: cyclin D1 and EMS1 are two new candidate oncogenes—a review. Gene 1995; 159: 83–96.

    CAS  PubMed  Google Scholar 

  16. Weaver AM . Cortactin in tumor invasiveness. Cancer Lett 2008; 265: 157–166.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Goswami S, Philippar U, Sun D, Patsialou A, Avraham J, Wang W et al. Identification of invasion specific splice variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo. Clin Exp Metastasis 2009; 26: 153–159.

    CAS  PubMed  Google Scholar 

  18. Philippar U, Roussos ET, Oser M, Yamaguchi H, Kim HD, Giampieri S et al. A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis. Dev Cell 2008; 15: 813–828.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Gertler F, Condeelis J . Metastasis: tumor cells becoming MENAcing. Trends Cell Biol 2011; 21: 81–90.

    CAS  PubMed  Google Scholar 

  20. Roussos ET, Wang Y, Wyckoff JB, Sellers RS, Wang W, Li J et al. Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors. Breast Cancer Res 2010; 12: R101.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Roussos ET, Balsamo M, Alford SK, Wyckoff JB, Gligorijevic B, Wang Y et al. Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer. J Cell Sci 2011; 124: 2120–2131.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Courtneidge SA, Azucena EF, Pass I, Seals DF, Tesfay L . The SRC substrate Tks5, podosomes (invadopodia), and cancer cell invasion. Cold Spring Harb Symp Quant Biol 2005; 70: 167–171.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  24. Eckert MA, Lwin TM, Chang AT, Kim J, Danis E, Ohno-Machado L et al. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell 2011; 19: 372–386.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Abram CL, Seals DF, Pass I, Salinsky D, Maurer L, Roth TM et al. The adaptor protein fish associates with members of the ADAMs family and localizes to podosomes of Src-transformed cells. J Biol Chem 2003; 278: 16844–16851.

    CAS  PubMed  Google Scholar 

  26. Oikawa T, Itoh T, Takenawa T . Sequential signals toward podosome formation in NIH-src cells. J Cell Biol 2008; 182: 157–169.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Crimaldi L, Courtneidge SA, Gimona M . Tks5 recruits AFAP-110, p190RhoGAP, and cortactin for podosome formation. Exp Cell Res 2009; 315: 2581–2592.

    CAS  PubMed  Google Scholar 

  28. Diaz B, Shani G, Pass I, Anderson D, Quintavalle M, Courtneidge SA . Tks5-dependent, nox-mediated generation of reactive oxygen species is necessary for invadopodia formation. Sci Signal 2009; 2: ra53.

    PubMed  PubMed Central  Google Scholar 

  29. Buschman MD, Bromann PA, Cejudo-Martin P, Wen F, Pass I, Courtneidge SA . The novel adaptor protein Tks4 (SH3PXD2B) is required for functional podosome formation. Mol Biol Cell 2009; 20: 1302–1311.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Blouw B, Seals DF, Pass I, Diaz B, Courtneidge SA . A role for the podosome/invadopodia scaffold protein Tks5 in tumor growth in vivo. Eur J Cell Biol 2008; 87: 555–567.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Overall CM, Kleifeld O . Tumour microenvironment—opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 2006; 6: 227–239.

    CAS  PubMed  Google Scholar 

  32. Freije JM, Balbin M, Pendas AM, Sanchez LM, Puente XS, Lopez-Otin C . Matrix metalloproteinases and tumor progression. Adv Exp Med Biol 2003; 532: 91–107.

    CAS  PubMed  Google Scholar 

  33. Yana I, Weiss SJ . Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases. Mol Biol Cell 2000; 11: 2387–2401.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ohuchi E, Imai K, Fujii Y, Sato H, Seiki M, Okada Y . Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol Chem 1997; 272: 2446–2451.

    CAS  PubMed  Google Scholar 

  35. d'Ortho MP, Will H, Atkinson S, Butler G, Messent A, Gavrilovic J et al. Membrane-type matrix metalloproteinases 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases. Eur J Biochem 1997; 250: 751–757.

    CAS  PubMed  Google Scholar 

  36. Fosang AJ, Last K, Fujii Y, Seiki M, Okada Y . Membrane-type 1 MMP (MMP-14) cleaves at three sites in the aggrecan interglobular domain. FEBS Lett 1998; 430: 186–190.

    CAS  PubMed  Google Scholar 

  37. Koshikawa N, Giannelli G, Cirulli V, Miyazaki K, Quaranta V . Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J Cell Biol 2000; 148: 615–624.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Deryugina EI, Ratnikov B, Monosov E, Postnova TI, DiScipio R, Smith JW et al. MT1-MMP initiates activation of pro-MMP-2 and integrin alphavbeta3 promotes maturation of MMP-2 in breast carcinoma cells. Exp Cell Res 2001; 263: 209–223.

    CAS  PubMed  Google Scholar 

  39. Toth M, Chvyrkova I, Bernardo MM, Hernandez-Barrantes S, Fridman R . Pro-MMP-9 activation by the MT1-MMP/MMP-2 axis and MMP-3: role of TIMP-2 and plasma membranes. Biochem Biophys Res Commun 2003; 308: 386–395.

    CAS  PubMed  Google Scholar 

  40. Yu X, Zech T, McDonald L, Gonzalez EG, Li A, Macpherson I et al. N-WASP coordinates the delivery and F-actin-mediated capture of MT1-MMP at invasive pseudopods. J Cell Biol 2012; 199: 527–544.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Steffen A, Le Dez G, Poincloux R, Recchi C, Nassoy P, Rottner K et al. MT1-MMP-dependent invasion is regulated by TI-VAMP/VAMP7. Curr Biol 2008; 18: 926–931.

    CAS  PubMed  Google Scholar 

  42. Bravo-Cordero JJ, Marrero-Diaz R, Megias D, Genis L, Garcia-Grande A, Garcia MA et al. MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway. EMBO J 2007; 26: 1499–1510.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Poincloux R, Lizarraga F, Chavrier P . Matrix invasion by tumour cells: a focus on MT1-MMP trafficking to invadopodia. J Cell Sci 2009; 122: 3015–3024.

    CAS  PubMed  Google Scholar 

  44. Nyalendo C, Beaulieu E, Sartelet H, Michaud M, Fontaine N, Gingras D et al. Impaired tyrosine phosphorylation of membrane type 1-matrix metalloproteinase reduces tumor cell proliferation in three-dimensional matrices and abrogates tumor growth in mice. Carcinogenesis 2008; 29: 1655–1664.

    CAS  PubMed  Google Scholar 

  45. Nyalendo C, Michaud M, Beaulieu E, Roghi C, Murphy G, Gingras D et al. Src-dependent phosphorylation of membrane type I matrix metalloproteinase on cytoplasmic tyrosine 573: role in endothelial and tumor cell migration. J Biol Chem 2007; 282: 15690–15699.

    CAS  PubMed  Google Scholar 

  46. Eisenach PA, de Sampaio PC, Murphy G, Roghi C . Membrane type 1 matrix metalloproteinase (MT1-MMP) ubiquitination at Lys581 increases cellular invasion through type I collagen. J Biol Chem 2012; 287: 11533–11545.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Egeblad M, Werb Z . New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002; 2: 161–174.

    CAS  PubMed  Google Scholar 

  48. Szabova L, Chrysovergis K, Yamada SS, Holmbeck K . MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease. Oncogene 2008; 27: 3274–3281.

    CAS  PubMed  Google Scholar 

  49. Perentes JY, Kirkpatrick ND, Nagano S, Smith EY, Shaver CM, Sgroi D et al. Cancer cell-associated MT1-MMP promotes blood vessel invasion and distant metastasis in triple-negative mammary tumors. Cancer Res 2011; 71: 4527–4538.

    CAS  PubMed  Google Scholar 

  50. Devy L, Dransfield DT . New strategies for the next generation of matrix-metalloproteinase inhibitors: selectively targeting membrane-anchored MMPs with therapeutic antibodies. Biochem Res Int 2011; 2011: 191670.

    PubMed  Google Scholar 

  51. Gialeli C, Theocharis AD, Karamanos NK . Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J 2011; 278: 16–27.

    CAS  PubMed  Google Scholar 

  52. Devy L, Huang L, Naa L, Yanamandra N, Pieters H, Frans N et al. Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis. Cancer Res 2009; 69: 1517–1526.

    CAS  PubMed  Google Scholar 

  53. Basu B, Correa de Sampaio P, Mohammed H, Fogarasi M, Corrie P, Watkins NA et al. Inhibition of MT1-MMP activity using functional antibody fragments selected against its hemopexin domain. Int J Biochem Cell Biol 2012; 44: 393–403.

    CAS  PubMed  Google Scholar 

  54. Seals DF, Courtneidge SA . The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev 2003; 17: 7–30.

    CAS  PubMed  Google Scholar 

  55. Kveiborg M, Albrechtsen R, Couchman JR, Wewer UM . Cellular roles of ADAM12 in health and disease. Int J Biochem Cell Biol 2008; 40: 1685–1702.

    CAS  PubMed  Google Scholar 

  56. Moss ML, Lambert MH . Shedding of membrane proteins by ADAM family proteases. Essays Biochem 2002; 38: 141–153.

    CAS  PubMed  Google Scholar 

  57. Albrechtsen R, Stautz D, Sanjay A, Kveiborg M, Wewer UM . Extracellular engagement of ADAM12 induces clusters of invadopodia with localized ectodomain shedding activity. Exp Cell Res 2011; 317: 195–209.

    CAS  PubMed  Google Scholar 

  58. Diaz B, Yuen A, Iizuka S, Higashiyama S, Courtneidge SA . Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia. J Cell Biol 2013; 201: 279–292.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Handbook of proteolytic enzymes, volumes 1, 2 and 3 Third edition Anticancer Res 2013; 33: 2345.

  60. Roy R, Wewer UM, Zurakowski D, Pories SE, Moses MA . ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. J Biol Chem 2004; 279: 51323–51330.

    CAS  PubMed  Google Scholar 

  61. Kveiborg M, Frohlich C, Albrechtsen R, Tischler V, Dietrich N, Holck P et al. A role for ADAM12 in breast tumor progression and stromal cell apoptosis. Cancer Res 2005; 65: 4754–4761.

    CAS  PubMed  Google Scholar 

  62. Roy R, Rodig S, Bielenberg D, Zurakowski D, Moses MA . ADAM12 transmembrane and secreted isoforms promote breast tumor growth: a distinct role for ADAM12-S protein in tumor metastasis. J Biol Chem 2011; 286: 20758–20768.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Meadows SA, Edosada CY, Mayeda M, Tran T, Quan C, Raab H et al. Ala657 and conserved active site residues promote fibroblast activation protein endopeptidase activity via distinct mechanisms of transition state stabilization. Biochemistry 2007; 46: 4598–4605.

    CAS  PubMed  Google Scholar 

  64. O'Brien P, O'Connor BF . Seprase: an overview of an important matrix serine protease. Biochim Biophys Acta 2008; 1784: 1130–1145.

    CAS  PubMed  Google Scholar 

  65. Ghersi G, Zhao Q, Salamone M, Yeh Y, Zucker S, Chen WT . The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices. Cancer Res 2006; 66: 4652–4661.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Mueller SC, Ghersi G, Akiyama SK, Sang QX, Howard L, Pineiro-Sanchez M et al. A novel protease-docking function of integrin at invadopodia. J Biol Chem 1999; 274: 24947–24952.

    CAS  PubMed  Google Scholar 

  67. Christiansen VJ, Jackson KW, Lee KN, McKee PA . Effect of fibroblast activation protein and alpha2-antiplasmin cleaving enzyme on collagen types I, III, and IV. Arch Biochem Biophys 2007; 457: 177–186.

    CAS  PubMed  Google Scholar 

  68. Busek P, Malik R, Sedo A . Dipeptidyl peptidase IV activity and/or structure homologues (DASH) and their substrates in cancer. Int J Biochem Cell Biol 2004; 36: 408–421.

    CAS  PubMed  Google Scholar 

  69. Chen D, Kennedy A, Wang JY, Zeng W, Zhao Q, Pearl M et al. Activation of EDTA-resistant gelatinases in malignant human tumors. Cancer Res 2006; 66: 9977–9985.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Santos AM, Jung J, Aziz N, Kissil JL, Pure E . Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest 2009; 119: 3613–3625.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Pure E . The road to integrative cancer therapies: emergence of a tumor-associated fibroblast protease as a potential therapeutic target in cancer. Expert Opin Ther Targets 2009; 13: 967–973.

    CAS  PubMed  Google Scholar 

  72. Henry LR, Lee HO, Lee JS, Klein-Szanto A, Watts P, Ross EA et al. Clinical implications of fibroblast activation protein in patients with colon cancer. Clin Cancer Res 2007; 13: 1736–1741.

    CAS  PubMed  Google Scholar 

  73. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 2010; 330: 827–830.

    CAS  PubMed  Google Scholar 

  74. Hofheinz RD, al-Batran SE, Hartmann F, Hartung G, Jager D, Renner C et al. Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Onkologie 2003; 26: 44–48.

    CAS  PubMed  Google Scholar 

  75. Narra K, Mullins SR, Lee HO, Strzemkowski-Brun B, Magalong K, Christiansen VJ et al. Phase II trial of single agent Val-boroPro (Talabostat) inhibiting Fibroblast Activation Protein in patients with metastatic colorectal cancer. Cancer Biol Ther 2007; 6: 1691–1699.

    CAS  PubMed  Google Scholar 

  76. Eager RM, Cunningham CC, Senzer NN, Stephenson J Jr., Anthony SP, O’Day SJ et al. Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma. BMC Cancer 2009; 9: 263.

    PubMed  PubMed Central  Google Scholar 

  77. Lee J, Fassnacht M, Nair S, Boczkowski D, Gilboa E . Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts. Cancer Res 2005; 65: 11156–11163.

    CAS  PubMed  Google Scholar 

  78. Loeffler M, Kruger JA, Niethammer AG, Reisfeld RA . Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest 2006; 116: 1955–1962.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Fischer E, Chaitanya K, Wuest T, Wadle A, Scott AM, van den Broek M et al. Radioimmunotherapy of fibroblast activation protein positive tumors by rapidly internalizing antibodies. Clin Cancer Res 2012; 18: 6208–6218.

    CAS  PubMed  Google Scholar 

  80. Summy JM, Gallick GE . Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev 2003; 22: 337–358.

    CAS  PubMed  Google Scholar 

  81. Chen WT, Chen JM, Parsons SJ, Parsons JT . Local degradation of fibronectin at sites of expression of the transforming gene product pp60src. Nature 1985; 316: 156–158.

    CAS  PubMed  Google Scholar 

  82. Balzer EM, Whipple RA, Thompson K, Boggs AE, Slovic J, Cho EH et al. c-Src differentially regulates the functions of microtentacles and invadopodia. Oncogene 2010; 29: 6402–6408.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Kelley LC, Ammer AG, Hayes KE, Martin KH, Machida K, Jia L et al. Oncogenic Src requires a wild-type counterpart to regulate invadopodia maturation. J Cell Sci 2010; 123: 3923–3932.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Mader CC, Oser M, Magalhaes MA, Bravo-Cordero JJ, Condeelis J, Koleske AJ et al. An EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Cancer Res 2011; 71: 1730–1741.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Chan PC, Chen HC . p120RasGAP-mediated activation of c-Src is critical for oncogenic Ras to induce tumor invasion. Cancer Res 2012; 72: 2405–2415.

    CAS  PubMed  Google Scholar 

  86. Sanchez-Bailon MP, Calcabrini A, Gomez-Dominguez D, Morte B, Martin-Forero E, Gomez-Lopez G et al. Src kinases catalytic activity regulates proliferation, migration and invasiveness of MDA-MB-231 breast cancer cells. Cell Signal 2012; 24: 1276–1286.

    CAS  PubMed  Google Scholar 

  87. Yeatman TJ . A renaissance for SRC. Nat Rev Cancer 2004; 4: 470–480.

    CAS  PubMed  Google Scholar 

  88. Ishizawar R, Parsons SJ . c-Src and cooperating partners in human cancer. Cancer Cell 2004; 6: 209–214.

    CAS  PubMed  Google Scholar 

  89. Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 2009; 16: 67–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Aligayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA, Gallick GE . Activation of Src kinase in primary colorectal carcinoma: an indicator of poor clinical prognosis. Cancer 2002; 94: 344–351.

    PubMed  Google Scholar 

  91. Wang S, Yuan Y, Liao L, Kuang SQ, Tien JC, O'Malley BW et al. Disruption of the SRC-1 gene in mice suppresses breast cancer metastasis without affecting primary tumor formation. Proc Natl Acad Sci USA 2009; 106: 151–156.

    CAS  PubMed  Google Scholar 

  92. Trevino JG, Summy JM, Lesslie DP, Parikh NU, Hong DS, Lee FY et al. Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am J Pathol 2006; 168: 962–972.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Puls LN, Eadens M, Messersmith W . Current status of SRC inhibitors in solid tumor malignancies. Oncologist 2010; 16: 566–578.

    Google Scholar 

  94. Anbalagan M, Carrier L, Glodowski S, Hangauer D, Shan B, Rowan BG . KX-01, a novel Src kinase inhibitor directed toward the peptide substrate site, synergizes with tamoxifen in estrogen receptor alpha positive breast cancer. Breast Cancer Res Treat 2012; 132: 391–409.

    CAS  PubMed  Google Scholar 

  95. Naing A, Cohen R, Dy GK, Hong DS, Dyster L, Hangauer DG et al. A phase I trial of KX2-391, a novel non-ATP competitive substrate-pocket- directed SRC inhibitor, in patients with advanced malignancies. Invest New Drugs 2013; 31: 967–973.

    CAS  PubMed  Google Scholar 

  96. Lin J, Arlinghaus R . Activated c-Abl tyrosine kinase in malignant solid tumors. Oncogene 2008; 27: 4385–4391.

    CAS  PubMed  Google Scholar 

  97. Srinivasan D, Plattner R . Activation of Abl tyrosine kinases promotes invasion of aggressive breast cancer cells. Cancer Res 2006; 66: 5648–5655.

    CAS  PubMed  Google Scholar 

  98. Plattner R, Kadlec L, DeMali KA, Kazlauskas A, Pendergast AM . c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF. Genes Dev 1999; 13: 2400–2411.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Smith-Pearson PS, Greuber EK, Yogalingam G, Pendergast AM . Abl kinases are required for invadopodia formation and chemokine-induced invasion. J Biol Chem 2010; 285: 40201–40211.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Gil-Henn H, Patsialou A, Wang Y, Warren MS, Condeelis JS, Koleske AJ . Arg/Abl2 promotes invasion and attenuates proliferation of breast cancer in vivo. Oncogene 2013; 32: 2622–2630.

    CAS  PubMed  Google Scholar 

  101. Jallal H, Valentino ML, Chen G, Boschelli F, Ali S, Rabbani SA . A Src/Abl kinase inhibitor, SKI-606, blocks breast cancer invasion, growth, and metastasis in vitro and in vivo. Cancer Res 2007; 67: 1580–1588.

    CAS  PubMed  Google Scholar 

  102. Mayer EL, Krop IE . Advances in targeting SRC in the treatment of breast cancer and other solid malignancies. Clin Cancer Res 2010; 16: 3526–3532.

    CAS  PubMed  Google Scholar 

  103. Mueller SC, Chen WT . Cellular invasion into matrix beads: localization of beta 1 integrins and fibronectin to the invadopodia. J Cell Sci 1991; 99 (Pt 2): 213–225.

    CAS  PubMed  Google Scholar 

  104. Destaing O, Planus E, Bouvard D, Oddou C, Badowski C, Bossy V et al. beta1A integrin is a master regulator of invadosome organization and function. Mol Biol Cell 2010; 21: 4108–4119.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Branch KM, Hoshino D, Weaver AM . Adhesion rings surround invadopodia and promote maturation. Biol Open 2012; 1: 711–722.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Beaty BT, Sharma VP, Bravo-Cordero JJ, Simpson MA, Eddy RJ, Koleske AJ et al. beta1 integrin regulates Arg to promote invadopodial maturation and matrix degradation. Mol Biol Cell 2013; 24: 1661–1675.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Nakahara H, Nomizu M, Akiyama SK, Yamada Y, Yeh Y, Chen WT . A mechanism for regulation of melanoma invasion. Ligation of alpha6beta1 integrin by laminin G peptides. J Biol Chem 1996; 271: 27221–27224.

    CAS  PubMed  Google Scholar 

  108. Desgrosellier JS, Cheresh DA . Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010; 10: 9–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Huck L, Pontier SM, Zuo DM, Muller WJ . beta1-integrin is dispensable for the induction of ErbB2 mammary tumors but plays a critical role in the metastatic phase of tumor progression. Proc Natl Acad Sci USA 2010; 107: 15559–15564.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Thiery JP, Acloque H, Huang RY, Nieto MA . Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139: 871–890.

    CAS  PubMed  Google Scholar 

  111. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004; 117: 927–939.

    CAS  PubMed  Google Scholar 

  112. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J . Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 2012; 22: 725–736.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Zavadil J, Bottinger EP . TGF-β and epithelial-to-mesenchymal transitions. Oncogene 2005; 24: 5764–5774.

    CAS  PubMed  Google Scholar 

  114. Pignatelli J, Tumbarello DA, Schmidt RP, Turner CE . Hic-5 promotes invadopodia formation and invasion during TGF-beta-induced epithelial-mesenchymal transition. J Cell Biol 2012; 197: 421–437.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 2009; 139: 891–906.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Parekh A, Weaver AM . Regulation of cancer invasiveness by the physical extracellular matrix environment. Cell Adh Migr 2009; 3: 288–292.

    PubMed  PubMed Central  Google Scholar 

  117. Ramaswamy S, Ross KN, Lander ES, Golub TR . A molecular signature of metastasis in primary solid tumors. Nat Genet 2003; 33: 49–54.

    CAS  PubMed  Google Scholar 

  118. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 2005; 8: 241–254.

    CAS  PubMed  Google Scholar 

  119. Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006; 440: 1222–1226.

    CAS  PubMed  Google Scholar 

  120. Alexander NR, Branch KM, Parekh A, Clark ES, Iwueke IC, Guelcher SA et al. Extracellular matrix rigidity promotes invadopodia activity. Curr Biol 2008; 18: 1295–1299.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Parekh A, Ruppender NS, Branch KM, Sewell-Loftin MK, Lin J, Boyer PD et al. Sensing and modulation of invadopodia across a wide range of rigidities. Biophys J 2011; 100: 573–582.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Yamaguchi H . Pathological roles of invadopodia in cancer invasion and metastasis. Eur J Cell Biol 2012; 91: 902–907.

    CAS  PubMed  Google Scholar 

  123. Gligorijevic B, Wyckoff J, Yamaguchi H, Wang Y, Roussos ET, Condeelis J . N-WASP-mediated invadopodium formation is involved in intravasation and lung metastasis of mammary tumors. J Cell Sci 2012; 125: 724–734.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Yamaguchi H, Wyckoff J, Condeelis J . Cell migration in tumors. Curr Opin Cell Biol 2005; 17: 559–564.

    CAS  PubMed  Google Scholar 

  125. Ito S, Nakanishi H, Ikehara Y, Kato T, Kasai Y, Ito K et al. Real-time observation of micrometastasis formation in the living mouse liver using a green fluorescent protein gene-tagged rat tongue carcinoma cell line. Int J Cancer 2001; 93: 212–217.

    CAS  PubMed  Google Scholar 

  126. Stoletov K, Kato H, Zardouzian E, Kelber J, Yang J, Shattil S et al. Visualizing extravasation dynamics of metastatic tumor cells. J Cell Sci 2010; 123: 2332–2341.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Steeg PS . Perspective: the right trials. Nature 2012; 485: S58–S59.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to the many researchers in this field whose work we were unable to cite due to space restrictions. Our research on tumor metastasis is supported by grants from National Institutes of Health 1DP2OD002420, National Cancer Institute 1RO1CA168689, American Cancer Society grant RSG-09-282-01-CSM, The Hartwell Foundation and DOD Breast Cancer Program W81XWH-13-1-0132 to JY, by the NIH IRACDA training grant 5K12GM068524 to HP, and by the NIH Pre-doctoral Training grant in Pharmaceutical Science 5T32GM007752 to NP.

Author information

Author notes

  1. H Paz and N Pathak: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA

    H Paz, N Pathak & J Yang

  2. Biomedical Sciences Program, University of California, San Diego, La Jolla, CA, USA

    N Pathak & J Yang

  3. Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA

    J Yang

Authors
  1. H Paz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N Pathak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Yang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paz, H., Pathak, N. & Yang, J. Invading one step at a time: the role of invadopodia in tumor metastasis. Oncogene 33, 4193–4202 (2014). https://doi.org/10.1038/onc.2013.393

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.393

Keywords

This article is cited by

Search

Advanced search

Quick links