The motility of both tumour and normal host cells contributes to tumour metastasis at several steps, including breaching of basement membrane, escape from the primary tumour, migration to blood and lymphatic vessels, intravasation and extravasation and movement into distant organs. The ability to migrate towards favourable environments is a fundamental and evolutionarily conserved cellular behaviour from unicellular organisms to humans.
Both normal and cancer cells migrate using diverse modes including amoeboid, mesenchymal, epithelial, collective and individual. Simple model organisms also exhibit these diverse modes of motility and offer experimental advantages such as low cost, amenability to large-scale genetic and pharmacological screening and live imaging of cells interacting within their native environments.
Studies of the social amoeba Dictyostelium discoideum have unravelled the complex signalling networks that mediate chemokine-directed cell migration, which is also observed with human immune and tumour cells.
The combination of high-resolution live imaging and genetic screening in the nematode has revealed that cells can breach a basement membrane by pushing the matrix aside and also by degrading it. This potentially offers a new mechanism to target cancer invasion therapeutically.
Cooperative, collective cell motility appears to contribute to tumour metastasis. Border cells in the Drosophila melanogaster ovary serve as a simple model that is genetically tractable and amenable to live imaging. This model has revealed that some mechanisms of cooperative, collective cell migration, such as the requirement for E-cadherin, differ from those of single-cell motility.
Direct modelling of metastasis can be carried out in both flies and fish. Work in flies has resulted in the identification and optimization of kinase inhibitors for metastatic thyroid cancer. The fish offers the lowest-cost vertebrate model for intravasation and extravasation studies and is amenable to live imaging as well as genetic and pharmacological manipulation.
Metastasis remains the greatest challenge in the clinical management of cancer. Cell motility is a fundamental and ancient cellular behaviour that contributes to metastasis and is conserved in simple organisms. In this Review, we evaluate insights relevant to human cancer that are derived from the study of cell motility in non-mammalian model organisms. Dictyostelium discoideum, Caenorhabditis elegans, Drosophila melanogaster and Danio rerio permit direct observation of cells moving in complex native environments and lend themselves to large-scale genetic and pharmacological screening. We highlight insights derived from each of these organisms, including the detailed signalling network that governs chemotaxis towards chemokines; a novel mechanism of basement membrane invasion; the positive role of E-cadherin in collective direction-sensing; the identification and optimization of kinase inhibitors for metastatic thyroid cancer on the basis of work in flies; and the value of zebrafish for live imaging, especially of vascular remodelling and interactions between tumour cells and host tissues. While the motility of tumour cells and certain host cells promotes metastatic spread, the motility of tumour-reactive T cells likely increases their antitumour effects. Therefore, it is important to elucidate the mechanisms underlying all types of cell motility, with the ultimate goal of identifying combination therapies that will increase the motility of beneficial cells and block the spread of harmful cells.
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Seok, J. et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl Acad. Sci. USA 110, 3507–3512 (2013).
Ellis, H. M. & Horvitz, H. R. Genetic control of programmed cell death in the nematode C. elegans. Cell 44, 817–829 (1986).
Nüsslein-Volhard, C. & Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 287, 795–801 (1980).
Klein, C. A. Selection and adaptation during metastatic cancer progression. Nature 501, 365–372 (2013).
Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).
Jin, T., Xu, X. & Hereld, D. Chemotaxis, chemokine receptors and human disease. Cytokine 44, 1–8 (2008).
Charest, P. G. & Firtel, R. A. Big roles for small GTPases in the control of directed cell movement. Biochem. J. 401, 377–390 (2007).
Sarris, M. & Sixt, M. Navigating in tissue mazes: chemoattractant interpretation in complex environments. Curr. Opin. Cell Biol. 36, 93–102 (2015).
Te Boekhorst, V., Preziosi, L. & Friedl, P. Plasticity of cell migration in vivo and in silico. Annu. Rev. Cell Dev. Biol. 32, 491–526 (2016).
Lauffenburger, D. A. & Horwitz, A. F. Cell migration: a physically integrated molecular process. Cell 84, 359–369 (1996).
Montell, D. J. Morphogenetic cell movements: diversity from modular mechanical properties. Science 322, 1502–1505 (2008).
Riveline, D. et al. Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism. J. Cell Biol. 153, 1175–1186 (2001).
Schmidt, S. & Friedl, P. Interstitial cell migration: integrin-dependent and alternative adhesion mechanisms. Cell Tissue Res. 339, 83–92 (2010).
Lämmermann, T. & Sixt, M. Mechanical modes of “amoeboid” cell migration. Curr. Opin. Cell Biol. 21, 636–644 (2009).
Paluch, E. K. & Raz, E. The role and regulation of blebs in cell migration. Curr. Opin. Cell Biol. 25, 582–590 (2013).
Lämmermann, T. et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453, 51–55 (2008).
Friedl, P. & Wolf, K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat. Rev. Cancer 3, 362–374 (2003).
Haeger, A., Wolf, K., Zegers, M. M. & Friedl, P. Collective cell migration: guidance principles and hierarchies. Trends Cell Biol. 25, 556–566 (2015).
Doyle, A. D., Wang, F. W., Matsumoto, K. & Yamada, K. M. One-dimensional topography underlies three-dimensional fibrillar cell migration. J. Cell Biol. 184, 481–490 (2009).
Weaver, V. M., Howlett, A. R., Langton-Webster, B., Petersen, O. W. & Bissell, M. J. The development of a functionally relevant cell culture model of progressive human breast cancer. Semin. Cancer Biol. 6, 175–184 (1995).
Wolf, K. et al. Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat. Cell Biol. 9, 893–904 (2007).
Friedl, P. & Wolf, K. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol. 188, 11–19 (2010).
Friedl, P., Sahai, E., Weiss, S. & Yamada, K. M. New dimensions in cell migration. Nat. Rev. Mol. Cell Biol. 13, 743–747 (2012).
Pickup, M. W., Mouw, J. K. & Weaver, V. M. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 15, 1243–1253 (2014).
Saxena, M. & Christofori, G. Rebuilding cancer metastasis in the mouse. Mol. Oncol. 7, 283–296 (2013).
Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Bloom, H. J. G. The value of histology in the prognosis and classification of breast cancer. Proc. R. Soc. Med. 51, 122–126 (1957).
Gordetsky, J. & Epstein, J. Grading of prostatic adenocarcinoma: current state and prognostic implications. Diagn. Pathol. 11, 25 (2016).
Müller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).
Qian, B.-Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).
Shields, J. D. et al. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11, 526–538 (2007).
Sceneay, J., Smyth, M. J. & Möller, A. The pre-metastatic niche: finding common ground. Cancer Metastasis Rev. 32, 449–464 (2013).
Artemenko, Y., Lampert, T. J. & Devreotes, P. N. Moving towards a paradigm: common mechanisms of chemotactic signaling in Dictyostelium and mammalian leukocytes. Cell. Mol. Life Sci. 71, 3711–3747 (2014).
Eichinger, L. et al. The genome of the social amoeba Dictyostelium discoideum. Nature 435, 43–57 (2005).
Chisholm, R. L. & Firtel, R. A. Insights into morphogenesis from a simple developmental system. Nat. Rev. Mol. Cell Biol. 5, 531–541 (2004).
Nichols, J. M., Veltman, D. & Kay, R. R. Chemotaxis of a model organism: progress with Dictyostelium. Curr. Opin. Cell Biol. 36, 7–12 (2015).
Roussos, E. T., Condeelis, J. S. & Patsialou, A. Chemotaxis in cancer. Nat. Rev. Cancer 11, 573–587 (2011).
Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).
Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015).
Ruffell, B., Affara, N. I. & Coussens, L. M. Differential macrophage programming in the tumor microenvironment. Trends Immunol. 33, 119–126 (2012).
Sica, A., Schioppa, T., Mantovani, A. & Allavena, P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur. J. Cancer 42, 717–727 (2006).
Swaney, K. F., Huang, C.-H. & Devreotes, P. N. Eukaryotic chemotaxis: a network of signaling pathways controls motility, directional sensing, and polarity. Annu. Rev. Biophys. 39, 265–289 (2010).
Parent, C. A. & Devreotes, P. N. A cell's sense of direction. Science 284, 765–770 (1999).
Xiao, Z., Zhang, N., Murphy, D. B. & Devreotes, P. N. Dynamic distribution of chemoattractant receptors in living cells during chemotaxis and persistent stimulation. J. Cell Biol. 139, 365–374 (1997).
Jin, T., Zhang, N., Long, Y., Parent, C. A. & Devreotes, P. N. Localization of the G protein betagamma complex in living cells during chemotaxis. Science 287, 1034–1036 (2000).
Parent, C. A., Blacklock, B. J., Froehlich, W. M., Murphy, D. B. & Devreotes, P. N. G protein signaling events are activated at the leading edge of chemotactic cells. Cell 95, 81–91 (1998). This work establishes D. discoideum as a model for imaging key biochemical events underlying chemotaxis at the leading edge using a novel biosensor for G protein signalling.
Servant, G. et al. Polarization of chemoattractant receptor signaling during neutrophil chemotaxis. Science 287, 1037–1040 (2000).
Schneider, I. C. & Haugh, J. M. Quantitative elucidation of a distinct spatial gradient-sensing mechanism in fibroblasts. J. Cell Biol. 171, 883–892 (2005).
Bear, J. E. & Haugh, J. M. Directed migration of mesenchymal cells: where signaling and the cytoskeleton meet. Curr. Opin. Cell Biol. 30, 74–82 (2014).
Iijima, M. & Devreotes, P. Tumor suppressor PTEN mediates sensing of chemoattractant gradients. Cell 109, 599–610 (2002). This paper demonstrates the key role of the PTEN tumour suppressor in chemotaxis.
Funamoto, S., Meili, R., Lee, S., Parry, L. & Firtel, R. A. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 109, 611–623 (2002).
Bagorda, A. & Parent, C. A. Eukaryotic chemotaxis at a glance. J. Cell Sci. 121, 2621–2624 (2008).
Comer, F. I. & Parent, C. A. PI 3-kinases and PTEN: how opposites chemoattract. Cell 109, 541–544 (2002).
Mayer, I. A. & Arteaga, C. L. The PI3K/AKT pathway as a target for cancer treatment. Annu. Rev. Med. 67, 11–28 (2016).
Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer 9, 550–562 (2009).
Jongsma, M., Matas-Rico, E., Rzadkowski, A., Jalink, K. & Moolenaar, W. H. LPA is a chemorepellent for B16 melanoma cells: action through the cAMP-elevating LPA5 receptor. PLoS ONE 6, e29260 (2011).
Shukla, S. et al. Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int. J. Cancer 121, 1424–1432 (2007).
Kim, D. et al. Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J. 15, 1953–1962 (2001).
Hawkins, P. T. & Stephens, L. R. PI3K signalling in inflammation. Biochim. Biophys. Acta 1851, 882–897 (2015).
Zhang, S. & Yu, D. PI(3)king apart PTEN's role in cancer. Clin. Cancer Res. 16, 4325–4330 (2010).
Okkenhaug, K., Graupera, M. & Vanhaesebroeck, B. Targeting PI3K in cancer: impact on tumor cells, their protective stroma, angiogenesis, and immunotherapy. Cancer Discov. 6, 1090–1105 (2016).
Rericha, E. C. & Parent, C. A. Steering in quadruplet: the complex signaling pathways directing chemotaxis. Sci. Signal. 1, e26 (2008).
Brzostowski, J. A. et al. Phosphorylation of chemoattractant receptors regulates chemotaxis, actin reorganization and signal relay. J. Cell Sci. 126, 4614–4626 (2013).
van Zijl, F., Krupitza, G. & Mikulits, W. Initial steps of metastasis: cell invasion and endothelial transmigration. Mutat. Res. 728, 23–34 (2011).
Yilmaz, M. & Christofori, G. Mechanisms of motility in metastasizing cells. Mol. Cancer Res. 8, 629–642 (2010).
Arshad, N. & Visweswariah, S. S. The multiple and enigmatic roles of guanylyl cyclase C in intestinal homeostasis. FEBS Lett. 586, 2835–2840 (2012).
Cybulski, N. & Hall, M. N. TOR complex 2: a signaling pathway of its own. Trends Biochem. Sci. 34, 620–627 (2009).
Park, J. B. et al. Phospholipase signalling networks in cancer. Nat. Rev. Cancer 12, 782–792 (2012).
Choi, J. W. et al. LPA receptors: subtypes and biological actions. Annu. Rev. Pharmacol. Toxicol. 50, 157–186 (2010).
Motz, G. T. & Coukos, G. Deciphering and reversing tumor immune suppression. Immunity 39, 61–73 (2013).
Rowe, R. G. & Weiss, S. J. Breaching the basement membrane: who, when and how? Trends Cell Biol. 18, 560–574 (2008).
Sherwood, D. R. & Sternberg, P. W. Anchor cell invasion into the vulval epithelium in C. elegans. Dev. Cell 5, 21–31 (2003). This work establishes C. elegans as a powerful model for cells crossing basement membranes owing to the exceptionally clear live imaging.
Sherwood, D. R. Cell invasion through basement membranes: an anchor of understanding. Trends Cell Biol. 16, 250–256 (2006).
Matus, D. Q. et al. Invasive cell fate requires G1 cell-cycle arrest and histone deacetylase-mediated changes in gene expression. Dev. Cell 35, 162–174 (2015).
Sherwood, D. R., Butler, J. A., Kramer, J. M. & Sternberg, P. W. FOS-1 promotes basement-membrane removal during anchor-cell invasion in C. elegans. Cell 121, 951–962 (2005). This work uses genetic screening and live imaging to dissect molecular pathways of basement membrane removal in C. elegans with unprecedented clarity and precision.
Ozanne, B. W., Spence, H. J., McGarry, L. C. & Hennigan, R. F. Transcription factors control invasion: AP-1 the first among equals. Oncogene 26, 1–10 (2007).
Hastie, E. L. & Sherwood, D. R. A new front in cell invasion: The invadopodial membrane. Eur. J. Cell Biol. 95, 441–448 (2016).
Lohmer, L. L. et al. A sensitized screen for genes promoting invadopodia function in vivo: CDC-42 and Rab GDI-1 direct distinct aspects of invadopodia formation. PLoS Genet. 12, e1005786 (2016). This work exploits the power of C. elegans genetics to identify key genes required for invadopodia formation and function in vivo.
Hagedorn, E. J. et al. The netrin receptor DCC focuses invadopodia-driven basement membrane transmigration in vivo. J. Cell Biol. 201, 903–913 (2013).
Murphy, D. A. & Courtneidge, S. A. The “ins” and “outs” of podosomes and invadopodia: characteristics, formation and function. Nat. Rev. Mol. Cell Biol. 12, 413–426 (2011).
Castro-Castro, A. et al. Cellular and molecular mechanisms of MT1-MMP-dependent cancer cell invasion. Annu. Rev. Cell Dev. Biol. 32, 555–576 (2016).
Foxall, E., Pipili, A., Jones, G. E. & Wells, C. M. Significance of kinase activity in the dynamic invadosome. Eur. J. Cell Biol. 95, 483–492 (2016).
Pozzi, A., Yurchenco, P. D. & Iozzo, R. V. The nature and biology of basement membranes. Matrix Biol. 57–58, 1–11 (2017).
Kelley, L. C., Lohmer, L. L., Hagedorn, E. J. & Sherwood, D. R. Traversing the basement membrane in vivo: a diversity of strategies. J. Cell Biol. 204, 291–302 (2014).
Glentis, A. et al. Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane. Nat. Commun. 8, 924 (2017).
Kessenbrock, K., Wang, C.-Y. & Werb, Z. Matrix metalloproteinases in stem cell regulation and cancer. Matrix Biol. 44–46, 184–190 (2015).
Kessenbrock, K., Plaks, V. & Werb, Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52–67 (2010).
Corcoran, A. & Del Maestro, R. F. Testing the “Go or Grow” hypothesis in human medulloblastoma cell lines in two and three dimensions. Neurosurgery 53, 174–184 (2003).
Garay, T. et al. Cell migration or cytokinesis and proliferation? — revisiting the “go or grow” hypothesis in cancer cells in vitro. Exp. Cell Res. 319, 3094–3103 (2013).
Cheung, K. J., Gabrielson, E., Werb, Z. & Ewald, A. J. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155, 1639–1651 (2013).
Giese, A. et al. Dichotomy of astrocytoma migration and proliferation. Int. J. Cancer 67, 275–282 (1996).
Cheung, K. J. et al. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc. Natl Acad. Sci. USA 113, E854–E863 (2016).
Man, Y.-G. et al. Tumor-infiltrating immune cells promoting tumor invasion and metastasis: existing theories. J. Cancer 4, 84–95 (2013).
Ewald, A. J. Pulling cells out of tumours. Nat. Cell Biol. 19, 147–149 (2017).
Labernadie, A. et al. A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nat. Cell Biol. 19, 224–237 (2017).
Konen, J. et al. Image-guided genomics of phenotypically heterogeneous populations reveals vascular signalling during symbiotic collective cancer invasion. Nat. Commun. 8, 15078 (2017).
Theveneau, E. & Mayor, R. Collective cell migration of epithelial and mesenchymal cells. Cell. Mol. Life Sci. 70, 3481–3492 (2013).
Aceto, N. et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110–1122 (2014). This work demonstrates that circulating breast tumour cell clusters are more effective than single cells at colonizing distant sites.
Grigore, A. D., Jolly, M. K., Jia, D., Farach-Carson, M. C. & Levine, H. Tumor budding: the name is EMT. Partial EMT. J. Clin. Med. 5, 51 (2016).
Montell, D. J., Yoon, W. H. & Starz-Gaiano, M. Group choreography: mechanisms orchestrating the collective movement of border cells. Nat. Rev. Mol. Cell Biol. 13, 631–645 (2012).
Montell, D. J., Rorth, P. & Spradling, A. C. slow border cells, a locus required for a developmentally regulated cell migration during oogenesis, encodes Drosophila C/EBP. Cell 71, 51–62 (1992). This paper establishes D. melanogaster border cells as a genetic model for studying collective epithelial cell motility in vivo.
Silver, D. L. & Montell, D. J. Paracrine signaling through the JAK/STAT pathway activates invasive behavior of ovarian epithelial cells in Drosophila. Cell 107, 831–841 (2001). This work exploits the power of genetic screening in mosaic clones to show for the first time that JAK–STAT signalling is necessary and sufficient to activate motility within normal epithelial cells in vivo.
Starz-Gaiano, M., Melani, M., Wang, X., Meinhardt, H. & Montell, D. J. Feedback inhibition of Jak/STAT signaling by apontic is required to limit an invasive cell population. Dev. Cell 14, 726–738 (2008).
Yoon, W. H., Meinhardt, H. & Montell, D. J. miRNA-mediated feedback inhibition of JAK/STAT morphogen signalling establishes a cell fate threshold. Nat. Cell Biol. 13, 1062–1069 (2011).
Silver, D. L., Naora, H., Liu, J., Cheng, W. & Montell, D. J. Activated signal transducer and activator of transcription (STAT) 3: localization in focal adhesions and function in ovarian cancer cell motility. Cancer Res. 64, 3550–3558 (2004). This work demonstrates the role of STAT3 in cancer cell motility in vitro.
Yue, P. et al. Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells. Oncogene 31, 2309–2322 (2012).
Gu, L. et al. Stat5 promotes metastatic behavior of human prostate cancer cells in vitro and in vivo. Endocr. Relat. Cancer 17, 481–493 (2010).
Moser, C. et al. STAT5b as molecular target in pancreatic cancer — inhibition of tumor growth, angiogenesis, and metastases. Neoplasia 14, 915–925 (2012).
Niwa, Y. et al. Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 24, 6406–6417 (2005).
Chuang, C.-H. et al. Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat. Med. 23, 291–300 (2017).
Teng, Y., Ross, J. L. & Cowell, J. K. The involvement of JAK-STAT3 in cell motility, invasion, and metastasis. JAKSTAT 3, e28086 (2014).
Kuzet, S.-E. & Gaggioli, C. Fibroblast activation in cancer: when seed fertilizes soil. Cell Tissue Res. 365, 607–619 (2016).
Wang, X. et al. Analysis of cell migration using whole-genome expression profiling of migratory cells in the Drosophila ovary. Dev. Cell 10, 483–495 (2006).
Duchek, P., Somogyi, K., Jékely, G., Beccari, S. & Rørth, P. Guidance of cell migration by the Drosophila PDGF/VEGF receptor. Cell 107, 17–26 (2001).
McDonald, J. A., Pinheiro, E. M., Kadlec, L., Schupbach, T. & Montell, D. J. Multiple EGFR ligands participate in guiding migrating border cells. Dev. Biol. 296, 94–103 (2006).
McDonald, J. A., Pinheiro, E. M. & Montell, D. J. PVF1, a PDGF/VEGF homolog, is sufficient to guide border cells and interacts genetically with Taiman. Development 130, 3469–3478 (2003).
Duchek, P. & Rørth, P. Guidance of cell migration by EGF receptor signaling during Drosophila oogenesis. Science 291, 131–133 (2001).
Murphy, A. M. & Montell, D. J. Cell type-specific roles for Cdc42, Rac, and RhoL in Drosophila oogenesis. J. Cell Biol. 133, 617–630 (1996).
Ridley, A. J. Rho GTPase signalling in cell migration. Curr. Opin. Cell Biol. 36, 103–112 (2015).
Zegers, M. M. & Friedl, P. Rho GTPases in collective cell migration. Small GTPases 5, e28997 (2014).
Wang, X., He, L., Wu, Y. I., Hahn, K. M. & Montell, D. J. Light-mediated activation reveals a key role for Rac in collective guidance of cell movement in vivo. Nat. Cell Biol. 12, 591–597 (2010).
Fernández-Espartero, C. H. et al. GTP exchange factor Vav regulates guided cell migration by coupling guidance receptor signalling to local Rac activation. J. Cell Sci. 126, 2285–2293 (2013).
Ramel, D., Wang, X., Laflamme, C., Montell, D. J. & Emery, G. Rab11 regulates cell-cell communication during collective cell movements. Nat. Cell Biol. 15, 317–324 (2013).
Palamidessi, A. et al. Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration. Cell 134, 135–147 (2008).
Naora, H. & Montell, D. J. Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat. Rev. Cancer 5, 355–366 (2005).
Hou, J.-M. et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J. Clin. Oncol. 30, 525–532 (2012).
Maddipati, R. & Stanger, B. Z. Pancreatic cancer metastases harbor evidence of polyclonality. Cancer Discov. 5, 1086–1097 (2015).
Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015).
Niewiadomska, P., Godt, D. & Tepass, U. DE-Cadherin is required for intercellular motility during Drosophila oogenesis. J. Cell Biol. 144, 533–547 (1999). This work demonstrates a surprising requirement for E-cadherin-mediated adhesion between border cells and nurse cells during border cell migration.
Cai, D. et al. Mechanical feedback through E-cadherin promotes direction sensing during collective cell migration. Cell 157, 1146–1159 (2014). This study uses sophisticated genetics and live imaging to show that E-cadherin serves three distinct positive roles in promoting collective direction-sensing during border cell migration.
Desgrosellier, J. S. & Cheresh, D. A. Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 10, 9–22 (2010).
Cai, D. et al. Modeling and analysis of collective cell migration in an in vivo three-dimensional environment. Proc. Natl Acad. Sci. USA 113, E2134–E2141 (2016).
Cheung, K. J. & Ewald, A. J. A collective route to metastasis: seeding by tumor cell clusters. Science 352, 167–169 (2016).
Reinhold, W. C. et al. Multifactorial regulation of E-cadherin expression: an integrative study. Mol. Cancer Ther. 9, 1–16 (2010).
Jeanes, A., Gottardi, C. J. & Yap, A. S. Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene 27, 6920–6929 (2008).
Jolly, M. K., Ware, K. E., Gilja, S., Somarelli, J. A. & Levine, H. EMT and MET: necessary or permissive for metastasis? Mol. Oncol. 11, 755–769 (2017).
Rodriguez, F. J., Lewis-Tuffin, L. J. & Anastasiadis, P. Z. E-Cadherin's dark side: possible role in tumor progression. Biochim. Biophys. Acta 1826, 23–31 (2012).
Shamir, E. R. et al. Twist1-induced dissemination preserves epithelial identity and requires E-cadherin. J. Cell Biol. 204, 839–856 (2014).
Pinheiro, E. M. & Montell, D. J. Requirement for Par-6 and Bazooka in Drosophila border cell migration. Development 131, 5243–5251 (2004).
Sallak, Y., Torres, A. Y., Yin, H. & Montell, D. Src42A required for collective border cell migration in vivo. bioRxiv https://doi.org/10.1101/186049 (2017).
Serrels, A., Canel, M., Brunton, V. G. & Frame, M. C. Src/FAK-mediated regulation of E-cadherin as a mechanism for controlling collective cell movement: insights from in vivo imaging. Cell Adh. Migr. 5, 360–365 (2011).
Cai, D. & Montell, D. J. Diverse and dynamic sources and sinks in gradient formation and directed migration. Curr. Opin. Cell Biol. 30, 91–98 (2014).
Pocha, S. M. & Montell, D. J. Cellular and molecular mechanisms of single and collective cell migrations in Drosophila: themes and variations. Annu. Rev. Genet. 48, 295–318 (2014).
Kunwar, P. S., Siekhaus, D. E. & Lehmann, R. In vivo migration: a germ cell perspective. Annu. Rev. Cell Dev. Biol. 22, 237–265 (2006).
Bae, Y.-K., Trisnadi, N., Kadam, S. & Stathopoulos, A. The role of FGF signaling in guiding coordinate movement of cell groups: guidance cue and cell adhesion regulator? Cell Adh. Migr. 6, 397–403 (2012).
Ratheesh, A., Belyaeva, V. & Siekhaus, D. E. Drosophila immune cell migration and adhesion during embryonic development and larval immune responses. Curr. Opin. Cell Biol. 36, 71–79 (2015).
Evans, I. R. & Wood, W. Drosophila blood cell chemotaxis. Curr. Opin. Cell Biol. 30, 1–8 (2014).
Trisnadi, N. & Stathopoulos, A. Ectopic expression screen identifies genes affecting Drosophila mesoderm development including the HSPG Trol. G3 5, 301–313 (2015).
Heisenberg, C.-P. Dorsal closure in Drosophila: cells cannot get out of the tight spot. Bioessays 31, 1284–1287 (2009).
Andrew, D. J. & Ewald, A. J. Morphogenesis of epithelial tubes: Insights into tube formation, elongation, and elaboration. Dev. Biol. 341, 34–55 (2010).
Bischoff, M. Lamellipodia-based migrations of larval epithelial cells are required for normal closure of the adult epidermis of Drosophila. Dev. Biol. 363, 179–190 (2012).
Gateff, E. Malignant neoplasms of genetic origin in Drosophila melanogaster. Science 200, 1448–1459 (1978). This study establishes D. melanogaster as a tumour model and demonstrates that mutations can cause neoplasms in this organism.
Elsum, I., Yates, L., Humbert, P. O. & Richardson, H. E. The Scribble-Dlg-Lgl polarity module in development and cancer: from flies to man. Essays Biochem. 53, 141–168 (2012).
Bilder, D., Li, M. & Perrimon, N. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289, 113–116 (2000).
Bilder, D. & Perrimon, N. Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature 403, 676–680 (2000).
Campanale, J. P., Sun, T. Y. & Montell, D. J. Development and dynamics of cell polarity at a glance. J. Cell Sci. 130, 1201–1207 (2017).
Halaoui, R. & McCaffrey, L. Rewiring cell polarity signaling in cancer. Oncogene 34, 939–950 (2015).
Feigin, M. E. et al. Mislocalization of the cell polarity protein scribble promotes mammary tumorigenesis and is associated with basal breast cancer. Cancer Res. 74, 3180–3194 (2014).
Lin, W.-H., Asmann, Y. W. & Anastasiadis, P. Z. Expression of polarity genes in human cancer. Cancer Inform. 14, 15–28 (2015).
Vaira, V. et al. Aberrant overexpression of the cell polarity module scribble in human cancer. Am. J. Pathol. 178, 2478–2483 (2011).
Zhan, L. et al. Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell 135, 865–878 (2008).
Roberts, A. B. & Wakefield, L. M. The two faces of transforming growth factor beta in carcinogenesis. Proc. Natl Acad. Sci. USA 100, 8621–8623 (2003).
Pagliarini, R. A. & Xu, T. A genetic screen in Drosophila for metastatic behavior. Science 302, 1227–1231 (2003).
Brumby, A. M. & Richardson, H. E. scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769–5779 (2003). References 164 and 165 establish D. melanogaster as a model for genetic screening for mutations that promote the spread of cells expressing oncogenic Ras or Notch throughout the fly larva.
Wu, M., Pastor-Pareja, J. C. & Xu, T. Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature 463, 545–548 (2010).
Chi, C. et al. Disruption of lysosome function promotes tumor growth and metastasis in Drosophila. J. Biol. Chem. 285, 21817–21823 (2010).
Dhanasekaran, D. N. & Reddy, E. P. JNK signaling in apoptosis. Oncogene 27, 6245–6251 (2008).
Leong, G. R., Goulding, K. R., Amin, N., Richardson, H. E. & Brumby, A. M. Scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs. BMC Biol. 7, 62 (2009).
Igaki, T., Pagliarini, R. A. & Xu, T. Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr. Biol. 16, 1139–1146 (2006).
Sun, G. & Irvine, K. D. Ajuba family proteins link JNK to Hippo signaling. Sci. Signal. 6, ra81 (2013).
Rudrapatna, V. A., Bangi, E. & Cagan, R. L. Caspase signalling in the absence of apoptosis drives Jnk-dependent invasion. EMBO Rep. 14, 172–177 (2013).
Chen, F. JNK-induced apoptosis, compensatory growth, and cancer stem cells. Cancer Res. 72, 379–386 (2012).
Read, R. D. et al. A Drosophila model of multiple endocrine neoplasia type 2. Genetics 171, 1057–1081 (2005). This study establishes that D. melanogaster , improbably, serves as a model for multiple endocrine neoplasia type 2 (MEN2).
Das, T. K. & Cagan, R. L. A. Drosophila approach to thyroid cancer therapeutics. Drug Discov. Today Technol. 10, e65–71 (2013).
Dar, A. C., Das, T. K., Shokat, K. M. & Cagan, R. L. Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature 486, 80–84 (2012). This study demonstrates the power of D. melanogaster to identify a kinase inhibitor that when used in combination with inhibitors of other targets renders it more effective and safer than another drug already in clinical use for MEN2.
Sonoshita, M. & Cagan, R. L. Modeling human cancers in drosophila. Curr. Top. Dev. Biol. 121, 287–309 (2017).
Figueroa-Clarevega, A. & Bilder, D. Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting. Dev. Cell 33, 47–55 (2015).
Kwon, Y. et al. Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2. Dev. Cell 33, 36–46 (2015). References 178 and 179 show that D. melanogaster can model systemic features such as cachexia.
Petrie, R. J. & Yamada, K. M. Multiple mechanisms of 3D migration: the origins of plasticity. Curr. Opin. Cell Biol. 42, 7–12 (2016).
Zatulovskiy, E., Tyson, R., Bretschneider, T. & Kay, R. R. Bleb-driven chemotaxis of Dictyostelium cells. J. Cell Biol. 204, 1027–1044 (2014).
Liu, Y.-J. et al. Confinement and low adhesion induce fast amoeboid migration of slow mesenchymal cells. Cell 160, 659–672 (2015).
Harvie, E. A. & Huttenlocher, A. Neutrophils in host defense: new insights from zebrafish. J. Leukoc. Biol. 98, 523–537 (2015).
Paksa, A. & Raz, E. Zebrafish germ cells: motility and guided migration. Curr. Opin. Cell Biol. 36, 80–85 (2015).
Blaser, H. et al. Transition from non-motile behaviour to directed migration during early PGC development in zebrafish. J. Cell Sci. 118, 4027–4038 (2005).
Meyen, D. et al. Dynamic filopodia are required for chemokine-dependent intracellular polarization during guided cell migration in vivo. elife 4, e05279 (2015).
Dumstrei, K., Mennecke, R. & Raz, E. Signaling pathways controlling primordial germ cell migration in zebrafish. J. Cell Sci. 117, 4787–4795 (2004).
Blaser, H. et al. Migration of zebrafish primordial germ cells: a role for myosin contraction and cytoplasmic flow. Dev. Cell 11, 613–627 (2006).
Tarbashevich, K., Reichman-Fried, M., Grimaldi, C. & Raz, E. Chemokine-dependent pH elevation at the cell front sustains polarity in directionally migrating zebrafish germ cells. Curr. Biol. 25, 1096–1103 (2015).
Charras, G. & Paluch, E. Blebs lead the way: how to migrate without lamellipodia. Nat. Rev. Mol. Cell Biol. 9, 730–736 (2008).
Bereiter-Hahn, J., Lück, M., Miebach, T., Stelzer, H. K. & Vöth, M. Spreading of trypsinized cells: cytoskeletal dynamics and energy requirements. J. Cell Sci. 96, 171–188 (1990).
Diz- Muñoz, A. et al. Steering cell migration by alternating blebs and actin-rich protrusions. BMC Biol. 14, 74 (2016).
Balzer, E. M. et al. Physical confinement alters tumor cell adhesion and migration phenotypes. FASEB J. 26, 4045–4056 (2012).
Stroka, K. M. & Konstantopoulos, K. Physical biology in cancer. 4. Physical cues guide tumor cell adhesion and migration. Am. J. Physiol, Cell Physiol. 306, C98–C109 (2014).
Ignatius, M. S., Hayes, M. & Langenau, D. M. In vivo imaging of cancer in zebrafish. Adv. Exp. Med. Biol. 916, 219–237 (2016).
Spaink, H. P. et al. Robotic injection of zebrafish embryos for high-throughput screening in disease models. Methods 62, 246–254 (2013).
Taylor, A. M. & Zon, L. I. Zebrafish tumor assays: the state of transplantation. Zebrafish 6, 339–346 (2009).
Zhao, S., Huang, J. & Ye, J. A fresh look at zebrafish from the perspective of cancer research. J. Exp. Clin. Cancer Res. 34, 80 (2015).
Starnes, T. W. & Huttenlocher, A. Neutrophil reverse migration becomes transparent with zebrafish. Adv. Hematol. 2012, 398640 (2012).
White, R. M. et al. Transparent adult zebrafish as a tool for in vivo transplantation analysis. Cell Stem Cell 2, 183–189 (2008). This paper discusses the use of transparent zebrafish as a xenograft model that allows visualization of tumour spread.
White, R., Rose, K. & Zon, L. Zebrafish cancer: the state of the art and the path forward. Nat. Rev. Cancer 13, 624–636 (2013).
Moore, J. C. et al. Single-cell imaging of normal and malignant cell engraftment into optically clear prkdc-null SCID zebrafish. J. Exp. Med. 213, 2575–2589 (2016).
Tang, Q. et al. Optimized cell transplantation using adult rag2 mutant zebrafish. Nat. Methods 11, 821–824 (2014).
Drabsch, Y., Snaar-Jagalska, B. E. & Dijke, P. Fish tales: The use of zebrafish xenograft human cancer cell models. Histol. Histopathol. 32, 673–686 (2017).
Mercatali, L. et al. Development of a patient-derived xenograft (PDX) of breast cancer bone metastasis in a zebrafish model. Int. J. Mol. Sci. 17, E1375 (2016). This paper demonstrates that patient-derived tumour tissue can be transplanted into zebrafish and that the behaviour of these xenografts reflects the clinical course of the patients' disease.
Gaudenzi, G. et al. Patient-derived xenograft in zebrafish embryos: a new platform for translational research in neuroendocrine tumors. Endocrine 57, 214–219 (2016).
Stoletov, K., Montel, V., Lester, R. D., Gonias, S. L. & Klemke, R. High-resolution imaging of the dynamic tumor cell vascular interface in transparent zebrafish. Proc. Natl Acad. Sci. USA 104, 17406–17411 (2007).
Reymond, N. et al. RhoC and ROCKs regulate cancer cell interactions with endothelial cells. Mol. Oncol. 9, 1043–1055 (2015).
Weis, S., Cui, J., Barnes, L. & Cheresh, D. Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J. Cell Biol. 167, 223–229 (2004).
Harney, A. S. et al. Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 5, 932–943 (2015).
Stoletov, K. et al. Visualizing extravasation dynamics of metastatic tumor cells. J. Cell Sci. 123, 2332–2341 (2010).
Hagedorn, E. J. et al. Integrin acts upstream of netrin signaling to regulate formation of the anchor cell's invasive membrane in C. elegans. Dev. Cell 17, 187–198 (2009).
Chen, M. B., Lamar, J. M., Li, R., Hynes, R. O. & Kamm, R. D. Elucidation of the roles of tumor integrin β1 in the extravasation stage of the metastasis cascade. Cancer Res. 76, 2513–2524 (2016).
Reymond, N. et al. Cdc42 promotes transendothelial migration of cancer cells through β1 integrin. J. Cell Biol. 199, 653–668 (2012).
Pagès, F. et al. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 29, 1093–1102 (2010).
Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).
Roh-Johnson, M. et al. Macrophage contact induces RhoA GTPase signaling to trigger tumor cell intravasation. Oncogene 33, 4203–4212 (2014).
Wyckoff, J. B. et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 67, 2649–2656 (2007).
Goswami, S. et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 65, 5278–5283 (2005).
Robinson, B. D. et al. Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin. Cancer Res. 15, 2433–2441 (2009).
He, S. et al. Neutrophil-mediated experimental metastasis is enhanced by VEGFR inhibition in a zebrafish xenograft model. J. Pathol. 227, 431–445 (2012).
Wang, J. et al. Novel mechanism of macrophage-mediated metastasis revealed in a zebrafish model of tumor development. Cancer Res. 75, 306–315 (2015).
Fior, R. et al. Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts. Proc. Natl Acad. Sci. USA 114, E8234–E8243 (2017).
Mezawa, Y. & Orimo, A. The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas. Cell Tissue Res. 365, 675–689 (2016).
Bernards, R. & Weinberg, R. A. A progression puzzle. Nature 418, 823 (2002). This paper supports the view that genes that drive tumour initiation and progression may overlap substantially.
Steeg, P. S. Targeting metastasis. Nat. Rev. Cancer 16, 201–218 (2016).
Kodura, M. A. & Souchelnytskyi, S. Breast carcinoma metastasis suppressor gene 1 (BRMS1): update on its role as the suppressor of cancer metastases. Cancer Metastasis Rev. 34, 611–618 (2015).
Nguyen, D. X. & Massagué, J. Genetic determinants of cancer metastasis. Nat. Rev. Genet. 8, 341–352 (2007).
Nguyen, D. X., Bos, P. D. & Massagué, J. Metastasis: from dissemination to organ-specific colonization. Nat. Rev. Cancer 9, 274–284 (2009). This paper proposes the view that metastasis genes can be identified.
Meehan, W. J. et al. Breast cancer metastasis suppressor 1 (BRMS1) forms complexes with retinoblastoma-binding protein 1 (RBP1) and the mSin3 histone deacetylase complex and represses transcription. J. Biol. Chem. 279, 1562–1569 (2004).
Horak, C. E. et al. Nm23-H1 suppresses metastasis by inhibiting expression of the lysophosphatidic acid receptor EDG2. Cancer Res. 67, 11751–11759 (2007).
Sahni, S. et al. The metastasis suppressor, N-myc downstream-regulated gene 1 (NDRG1), inhibits stress-induced autophagy in cancer cells. J. Biol. Chem. 289, 9692–9709 (2014).
Wessels, D., Lusche, D. F., Kuhl, S., Heid, P. & Soll, D. R. PTEN plays a role in the suppression of lateral pseudopod formation during Dictyostelium motility and chemotaxis. J. Cell Sci. 120, 2517–2531 (2007).
Lee, T. & Montell, D. J. Multiple Ras signals pattern the Drosophila ovarian follicle cells. Dev. Biol. 185, 25–33 (1997).
Dang, T. T., Prechtl, A. M. & Pearson, G. W. Breast cancer subtype-specific interactions with the microenvironment dictate mechanisms of invasion. Cancer Res. 71, 6857–6866 (2011).
Westcott, J. M. et al. An epigenetically distinct breast cancer cell subpopulation promotes collective invasion. J. Clin. Invest. 125, 1927–1943 (2015).
Edme, N., Downward, J., Thiery, J.-P. & Boyer, B. Ras induces NBT-II epithelial cell scattering through the coordinate activities of Rac and MAPK pathways. J. Cell Sci. 115, 2591–2601 (2002).
Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).
Tsuji, T., Ibaragi, S. & Hu, G. Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res. 69, 7135–7139 (2009).
Riihimäki, M., Hemminki, A., Sundquist, J. & Hemminki, K. Patterns of metastasis in colon and rectal cancer. Sci. Rep. 6, 29765 (2016).
Entenberg, D. et al. In vivo subcellular resolution optical imaging in the lung reveals early metastatic proliferation and motility. Intravital 4, e1086613 (2015).
Ramakrishna, R. & Rostomily, R. Seed, soil, and beyond: the basic biology of brain metastasis. Surg. Neurol. Int. 4, S256–S264 (2013).
Ren, G., Esposito, M. & Kang, Y. Bone metastasis and the metastatic niche. J. Mol. Med. 93, 1203–1212 (2015).
Peinado, H. et al. Pre-metastatic niches: organ-specific homes for metastases. Nat. Rev. Cancer 17, 302–317 (2017).
Avgustinova, A. et al. Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. Nat. Commun. 7, 10305 (2016).
Calvo, F. et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat. Cell Biol. 15, 637–646 (2013).
Melero, I., Rouzaut, A., Motz, G. T. & Coukos, G. T-Cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy. Cancer Discov. 4, 522–526 (2014).
Senbabaoglu, Y. et al. The landscape of T cell infiltration in human cancer and its association with antigen presenting gene expression. bioRxiv https://doi.org/10.1101/025908 (2015).
Nakaya, Y. & Sheng, G. EMT in developmental morphogenesis. Cancer Lett. 341, 9–15 (2013).
Thiery, J. P., Acloque, H., Huang, R. Y. J. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).
Zheng, X. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).
Fischer, K. R. et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472–476 (2015). References 251 and 252 show that, in contrast to established dogma, EMT is not necessary for metastasis of lung or pancreatic cancers but rather confers chemoresistance.
Steinestel, K., Eder, S., Schrader, A. J. & Steinestel, J. Clinical significance of epithelial-mesenchymal transition. Clin. Transl Med. 3, 17 (2014).
Bronsert, P. et al. Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface. J. Pathol. 234, 410–422 (2014).
The authors thank their anonymous reviewers for helpful suggestions and careful reading of the manuscript. This work was funded by the Intramural Research Program, National Cancer Institute, National Institutes of Health, by internal funding from the University of Michigan to C.A.P and by NIH grants R01GM73164 and R01GM46425 to D.J.M.
The authors declare no competing financial interests.
A quasi-two-dimensional structure localized at the leading edge of motile cells that contains a highly dynamic actin network.
A structure containing stable actin filaments and mature adhesion sites localized just behind the lamellipodium.
- Basement membrane
A thin, fibrous membrane that separates epithelium, mesothelium or endothelium from the underlying stroma.
A family of low molecular mass proteins that are secreted by various cells and regulate a variety of responses, including cell migration, morphogenesis and proliferation as well as angiogenesis by binding to G protein-coupled receptors.
- Matrix metalloproteinase
(MMP). Calcium-dependent, zinc-containing endopeptidases that degrade matrix proteins.
An embryonic tissue layer that differentiates into mesoderm and endoderm.
- Directional persistence
A measure commonly defined as the ratio of displacement to trajectory length.
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