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Molecular mechanisms of epithelial–mesenchymal transition

Key Points

  • The epithelial–mesenchymal transition (EMT) process results in the downregulation of epithelial, and activation of mesenchymal, cell characteristics and behaviour. This transdifferentiation process is initially reversible, with mesenchymal–epithelial transition (MET) enabling reversion to an epithelial phenotype. Both epithelial and endothelial cells can transition into a mesenchymal phenotype.

  • EMT is integral in development, starting with the generation of mesoderm, and consecutive waves of EMT and MET occur in the generation of diverse cell types and tissues. EMT is pathologically reactivated in, and contributes to, the progression of fibrosis and cancer. In carcinomas, EMT has been associated with the generation of invasive cells and acquisition of cancer stem cell properties.

  • EMT is initiated by the deconstruction of epithelial cell–cell junctions and apical–basal polarity, subsequently enabling the cells to establish a front–rear polarity, which is required for directional migration. Further changes in cell adhesion and membrane extrusions contribute to the increased cell motility following EMT.

  • Integral in the EMT process is the reprogramming of gene expression, that is, the repression of an epithelial gene expression pattern and the activation of genes that contribute to EMT and the mesenchymal phenotype. EMT-associated gene reprogramming involves key transcription factors with central roles in driving this transdifferentiation process.

  • Superimposed on the changes in gene expression are extensive and selective alterations in the splicing patterns of nascent transcripts, which are mediated by changes in splicing factor expression. In addition, an extensive network of microRNAs (miRNAs) represses the expression of EMT transcription factors and other targets; in some cases, miRNAs regulate EMT and MET through functional feedback mechanisms.

  • Transforming growth factor-β (TGFβ) family proteins are potent inducers of EMT, partly through the SMAD-mediated activation of EMT transcription factor expression and the subsequent SMAD-mediated control of their transcription activities. TGFβ family proteins also activate complementary non-SMAD signalling pathways that contribute to the induction and progression of EMT.

  • EMT is elaborated through the functional cooperation of signalling pathways that can be activated by diverse extracellular signals. These pathways converge at multiple levels, including at the level of gene reprogramming.

Abstract

The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial–mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix–loop–helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

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Figure 1: Cellular events during EMT.
Figure 2: Roles and regulation of major EMT transcription factors.
Figure 3: Molecular mechanisms of TGFβ-induced EMT.
Figure 4: Signalling pathways involved in EMT.

References

  1. Hay, E. D. An overview of epithelio-mesenchymal transformation. Acta Anat. 154, 8–20 (1995).

    Article  CAS  PubMed  Google Scholar 

  2. Thiery, J. P. & Sleeman, J. P. Complex networks orchestrate epithelial-mesenchymal transitions. Nature Rev. Mol. Cell Biol. 7, 131–142 (2006).

    Article  CAS  Google Scholar 

  3. Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chapman, H. A. Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu. Rev. Physiol. 73, 413–435 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Huang, R. Y., Guilford, P. & Thiery, J. P. Early events in cell adhesion and polarity during epithelial-mesenchymal transition. J. Cell Sci. 125, 4417–4422 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  8. Niehrs, C. The complex world of WNT receptor signalling. Nature Rev. Mol. Cell Biol. 13, 767–779 (2012).

    Article  CAS  Google Scholar 

  9. Kourtidis, A., Ngok, S. P. & Anastasiadis, P. Z. p120 catenin: an essential regulator of cadherin stability, adhesion-induced signaling, and cancer progression. Prog. Mol. Biol. Transl. Sci. 116, 409–432 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bax, N. A. et al. Epithelial-to-mesenchymal transformation alters electrical conductivity of human epicardial cells. J. Cell. Mol. Med. 15, 2675–2683 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Peinado, H., Olmeda, D. & Cano, A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nature Rev. Cancer 7, 415–428 (2007).

    Article  CAS  Google Scholar 

  12. De Craene, B. & Berx, G. Regulatory networks defining EMT during cancer initiation and progression. Nature Rev. Cancer 13, 97–110 (2013).

    Article  CAS  Google Scholar 

  13. St Johnston, D. & Ahringer, J. Cell polarity in eggs and epithelia: parallels and diversity. Cell 141, 757–774 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Navarro, C. et al. Junctional recruitment of mammalian Scribble relies on E-cadherin engagement. Oncogene 24, 4330–4339 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Qin, Y., Capaldo, C., Gumbiner, B. M. & Macara, I. G. The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J. Cell Biol. 171, 1061–1071 (2005). Silencing the expression of the polarity complex protein SCRIB results in loss of cell–cell adhesion, EMT and migration, similarly to silencing E-cadherin expression. These results illustrate the intimate functional linkage of epithelial cell adhesion and apical–basal polarity, and their roles in EMT.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Moreno-Bueno, G., Portillo, F. & Cano, A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 27, 6958–6969 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Yilmaz, M. & Christofori, G. Mechanisms of motility in metastasizing cells. Mol. Cancer Res. 8, 629–642 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Ridley, A. J. Life at the leading edge. Cell 145, 1012–1022 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. McNiven, M. A. Breaking away: matrix remodeling from the leading edge. Trends Cell Biol. 23, 16–21 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Haynes, J. Srivastava, J., Madson, N., Wittmann, T. & Barber, D. L. Dynamic actin remodeling during epithelial-mesenchymal transition depends on increased moesin expression. Mol. Biol. Cell 22, 4750–4764 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Narumiya, S., Tanji, M. & Ishizaki, T. Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev. 28, 65–76 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Whale, A., Hashim, F. N., Fram, S., Jones, G. E. & Wells, C. M. Signalling to cancer cell invasion through PAK family kinases. Front. Biosci. 16, 849–864 (2011).

    Article  CAS  Google Scholar 

  23. Anastasiadis, P. Z. & Reynolds, A. B. Regulation of Rho GTPases by p120-catenin. Curr. Opin. Cell Biol. 13, 604–610 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Nelson, W. J. Remodeling epithelial cell organization: transitions between front-rear and apical-basal polarity. Cold Spring Harb. Perspect Biol. 1, a000513 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Godde, N. J., Galea, R. C., Elsum, I. A. & Humbert, P. O. Cell polarity in motion: redefining mammary tissue organization through EMT and cell polarity transitions. J. Mammary Gland Biol. Neoplasia 15, 149–168 (2010).

    Article  PubMed  Google Scholar 

  26. Wittmann, T., Bokoch, G. M. & Waterman-Storer, C. M. Regulation of leading edge microtubule and actin dynamics downstream of Rac1. J. Cell Biol. 161, 845–851 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wheelock, M. J., Shintani, Y., Maeda, M., Fukumoto, Y. & Johnson, K. R. Cadherin switching. J. Cell Sci. 121, 727–735 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Theveneau, E. & Mayor, R. Cadherins in collective cell migration of mesenchymal cells. Curr. Opin. Cell Biol. 24, 677–684 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Brieher, W. M. & Yap, A. S. Cadherin junctions and their cytoskeleton(s). Curr. Opin. Cell Biol. 25, 39–46 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Hansen, S. M., Berezin, V. & Bock, E. Signaling mechanisms of neurite outgrowth induced by the cell adhesion molecules NCAM and N-cadherin. Cell. Mol. Life Sci. 65, 3809–3821 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Cavallaro, U. & Christofori, G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nature Rev. Cancer 4, 118–132 (2004).

    Article  CAS  Google Scholar 

  32. Lehembre, F. et al. NCAM-induced focal adhesion assembly: a functional switch upon loss of E-cadherin. EMBO J. 27, 2603–2615 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Toivola, D. M., Tao, G. Z., Habtezion, A., Liao, J. & Omary, M. B. Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments. Trends Cell Biol. 15, 608–617 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Mendez, M. G., Kojima, S. & Goldman, R. D. Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J. 24, 1838–1851 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang, X., Pursell, B., Lu, S., Chang, T. K. & Mercurio, A. M. Regulation of β4-integrin expression by epigenetic modifications in the mammary gland and during the epithelial-to-mesenchymal transition. J. Cell Sci. 122, 2473–2480 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kim, Y. et al. Integrin α3β1-dependent β-catenin phosphorylation links epithelial Smad signaling to cell contacts. J. Cell Biol. 184, 309–322 (2009). Illustrates the crucial role of an integrin, and the remarkable crosstalk and interdependence of signalling systems, in the control of EMT. Loss of a specific integrin impairs E-cadherin turnover and results in dysregulation of TGFβ signalling and β-catenin–SMAD cooperation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Maschler, S. et al. Tumor cell invasiveness correlates with changes in integrin expression and localization. Oncogene 24, 2032–2041 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Mise, N. et al. Zyxin is a transforming growth factor-β (TGF-β)/Smad3 target gene that regulates lung cancer cell motility via integrin α5β1. J. Biol. Chem. 287, 31393–31405 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Koenig, A., Mueller, C., Hasel, C., Adler, G. & Menke, A. Collagen type I induces disruption of E-cadherin-mediated cell-cell contacts and promotes proliferation of pancreatic carcinoma cells. Cancer Res. 66, 4662–4671 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Nistico, P., Bissell, M. J. & Radisky, D. C. Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. Cold Spring Harb Perspect Biol 4, a011908 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Radisky, D. C. et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436, 123–127 (2005). Provides a remarkable example of how the tumour microenvironment can induce EMT. Exposure of breast epithelial cells to the stromal matrix metalloprotease MMP3 induces the expression of an isoform of the RAC1 GTPase, and, in turn, an increase in cellular reactive oxygen species. This novel pathway activates the expression of SNAIL and the EMT programme.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shah, P. P., Fong, M. Y. & Kakar, S. S. PTTG induces EMT through integrin αvβ3-focal adhesion kinase signaling in lung cancer cells. Oncogene 31, 3124–3135 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Sheppard, D. Integrin-mediated activation of latent transforming growth factor β. Cancer Metastasis Rev. 24, 395–402 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Barrallo-Gimeno, A. & Nieto, M. A. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132, 3151–3161 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Xu, J., Lamouille, S. & Derynck, R. TGF-β-induced epithelial to mesenchymal transition. Cell Res. 19, 156–172 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Batlle, E. et al. The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature Cell Biol. 2, 84–89 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Cano, A. et al. The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biol. 2, 76–83 (2000). References 46 and 47 identify SNAIL as a repressor of E-cadherin expression and demonstrate that it promotes EMT in development and cancer by repressing the E-cadherin promoter.

    Article  CAS  PubMed  Google Scholar 

  48. Lin, T., Ponn, A., Hu, X., Law, B. K. & Lu, J. Requirement of the histone demethylase LSD1 in Snai1-mediated transcriptional repression during epithelial-mesenchymal transition. Oncogene 29, 4896–4904 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Peinado, H., Ballestar, E., Esteller, M. & Cano, A. Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol. Cell. Biol. 24, 306–319 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tong, Z. T. et al. EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin. Oncogene 31, 583–594 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Herranz, N. et al. Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol. Cell. Biol. 28, 4772–4781 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Dong, C. et al. Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer. Oncogene 32, 1351–1362 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Dong, C. et al. G9a interacts with Snail and is critical for Snail-mediated E-cadherin repression in human breast cancer. J. Clin. Invest. 122, 1469–1486 (2012). Histone methylation is shown to be crucial in the repression of E-cadherin expression, and in the initiation of EMT. The cooperation of SNAIL with a methyltransferase is shown to be essential in the control of this differentiation programme.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    CAS  PubMed  Google Scholar 

  55. Xi, Q. et al. A poised chromatin platform for TGF-β access to master regulators. Cell 147, 1511–1524 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jorda, M. et al. Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J. Cell Sci. 118, 3371–3385 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Vincent, T. et al. A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition. Nature Cell Biol. 11, 943–950 (2009). This study provides the first evidence at the molecular level for direct cooperation of TGFβ–SMAD signalling with a crucial EMT transcription factor, SNAIL1, in the initiation of EMT.

    Article  CAS  PubMed  Google Scholar 

  58. Zhou, B. P. et al. Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial-mesenchymal transition. Nature Cell Biol. 6, 931–940 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Yook, J. I. et al. A Wnt-Axin2-GSK3β cascade regulates Snail1 activity in breast cancer cells. Nature Cell Biol. 8, 1398–1406 (2006). Reference 58 and 59 demonstrate, in molecular detail, the regulation of SNAIL1 activity by GSK3β-mediated phosphorylation, and provide insight into the control of EMT by WNT signalling.

    Article  CAS  PubMed  Google Scholar 

  60. Sahlgren, C., Gustafsson, M. V., Jin, S., Poellinger, L. & Lendahl, U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc. Natl Acad. Sci. USA 105, 6392–6397 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Wu, Y. et al. Stabilization of Snail by NF-κB is required for inflammation-induced cell migration and invasion. Cancer Cell 15, 416–428 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wu, Y., Evers, B. M. & Zhou, B. P. Small C-terminal domain phosphatase enhances snail activity through dephosphorylation. J. Biol. Chem. 284, 640–648 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Du, C., Zhang, C., Hassan, S., Biswas, M. H. & Balaji, K. C. Protein kinase D1 suppresses epithelial-to-mesenchymal transition through phosphorylation of snail. Cancer Res. 70, 7810–7819 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Yang, Z. et al. Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions. Cancer Res. 65, 3179–3184 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Zhang, K. et al. Lats2 kinase potentiates Snail1 activity by promoting nuclear retention upon phosphorylation. EMBO J. 31, 29–43 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Wang, S. P. et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nature Cell Biol. 11, 694–704 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Yang, M. H. et al. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nature Cell Biol. 12, 982–992 (2010). The Polycomb complex protein BMI1, which is required for stem cell self-renewal, is shown to functionally cooperate with the EMT transcription factor TWIST1 in the repression of E-cadherin expression and in EMT. These results illustrate a role for chromatin remodelling in EMT.

    Article  CAS  PubMed  Google Scholar 

  68. Yang, M. H. et al. Direct regulation of TWIST by HIF-1α promotes metastasis. Nature Cell Biol. 10, 295–305 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Yang, F. et al. SET8 promotes epithelial-mesenchymal transition and confers TWIST dual transcriptional activities. EMBO J. 31, 110–123 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Farge, E. Mechanical induction of Twist in the Drosophila foregut/stomodeal primordium. Curr. Biol. 13, 1365–1377 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Kang, Y., Chen, C. R. & Massagué, J. A self-enabling TGFβ response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol. Cell 11, 915–926 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Hong, J. et al. Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. Cancer Res. 71, 3980–3990 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sanchez-Tillo, E. et al. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene 29, 3490–3500 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Postigo, A. A., Depp, J. L., Taylor, J. J. & Kroll, K. L. Regulation of Smad signaling through a differential recruitment of coactivators and corepressors by ZEB proteins. EMBO J. 22, 2453–2462 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang, J. et al. Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 446, 882–887 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Dave, N. et al. Functional cooperation between Snail1 and twist in the regulation of ZEB1 expression during epithelial to mesenchymal transition. J. Biol. Chem. 286, 12024–12032 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Shirakihara, T., Saitoh, M. & Miyazono, K. Differential regulation of epithelial and mesenchymal markers by δEF1 proteins in epithelial mesenchymal transition induced by TGF-β. Mol. Biol. Cell 18, 3533–3544 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Long, J., Zuo, D. & Park, M. Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin. J. Biol. Chem. 280, 35477–35489 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Eijkelenboom, A. & Burgering, B. M. FOXOs: signalling integrators for homeostasis maintenance. Nature Rev. Mol. Cell Biol. 14, 83–97 (2013).

    Article  CAS  Google Scholar 

  80. Bresnick, E. H., Lee, H. Y., Fujiwara, T., Johnson, K. D. & Keles, S. GATA switches as developmental drivers. J. Biol. Chem. 285, 31087–31093 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Campbell, K., Whissell, G., Franch-Marro, X., Batlle, E. & Casanova, J. Specific GATA factors act as conserved inducers of an endodermal-EMT. Dev. Cell 21, 1051–1061 (2011). A GATA transcription factor is found to have a crucial role in the induction of EMT, in Drosophila melanogaster and mammalian cells, through the downregulation of junctional E-cadherin, and repression of expression of the apical–basal polarity complex protein Crumbs.

    Article  CAS  PubMed  Google Scholar 

  82. Kondoh, H. & Kamachi, Y. SOX-partner code for cell specification: Regulatory target selection and underlying molecular mechanisms. Int. J. Biochem. Cell Biol. 42, 391–399 (2010).

    Article  CAS  PubMed  Google Scholar 

  83. Sakai, D., Suzuki, T., Osumi, N. & Wakamatsu, Y. Cooperative action of Sox9, Snail2 and PKA signaling in early neural crest development. Development 133, 1323–1333 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Guo, W. et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 148, 1015–1028 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Brown, R. L. et al. CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J. Clin. Invest. 121, 1064–1074 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Shirakihara, T. et al. TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition. EMBO J. 30, 783–795 (2011). TGFβ is shown to induce a switch in splicing patterns, specifically of FGF receptors, illustrating a role of differential splicing in the control of EMT. This study also highlights the functional crosstalk of TGFβ signalling with RTK signalling through the ERK MAPK pathway in defining the EMT phenotype.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Warzecha, C. C., Sato, T. K., Nabet, B., Hogenesch, J. B. & Carstens, R. P. ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Mol. Cell 33, 591–601 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yanagisawa, M. et al. A p120 catenin isoform switch affects Rho activity, induces tumor cell invasion, and predicts metastatic disease. J. Biol. Chem. 283, 18344–18354 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Shapiro, I. M. et al. An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet. 7, e1002218 (2011). Documents the extensive changes in splicing patterns that accompany EMT and the key roles of splicing mediators in the control of EMT. Analyses of the alternative splicing signature that defines EMT enable subtype classification of mammary carcinoma cells and tissues.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Warzecha, C. C. et al. An ESRP-regulated splicing programme is abrogated during the epithelial-mesenchymal transition. EMBO J. 29, 3286–3300 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Braeutigam, C. et al. The RNA-binding protein Rbfox2: an essential regulator of EMT-driven alternative splicing and a mediator of cellular invasion. Oncogene http://dx.doi.org/10.1038/onc.2013.50 (2013).

  92. Goncalves, V., Matos, P. & Jordan, P. Antagonistic SR proteins regulate alternative splicing of tumor-related Rac1b downstream of the PI3-kinase and Wnt pathways. Hum. Mol. Genet. 18, 3696–3707 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Valacca, C. et al. Sam68 regulates EMT through alternative splicing-activated nonsense-mediated mRNA decay of the SF2/ASF proto-oncogene. J. Cell Biol. 191, 87–99 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lamouille, S., Subramanyam, D., Blelloch, R. & Derynck, R. Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs. Curr. Opin. Cell Biol. 25, 200–207 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ru, P. et al. miRNA-29b suppresses prostate cancer metastasis by regulating epithelial-mesenchymal transition signaling. Mol. Cancer Ther. 11, 1166–1173 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Zhang, J. et al. miR-30 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in hepatocyte by targeting Snail1. Biochem. Biophys. Res. Commun. 417, 1100–1105 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Liu, Y. N. et al. MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms. Oncogene 32, 296–306 (2012). A mutually inhibitory loop, with miR-1 and miR-200 microRNAs repressing SNAIL2 expression, and SNAIL2 repressing miR-1 and miR-200 expression, is described. This double feedback mechanism enables for the gradual amplification of cancer-associated EMT.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Siemens, H. et al. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle 10, 4256–4271 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Moes, M. et al. A novel network integrating a miRNA-203/SNAI1 feedback loop which regulates epithelial to mesenchymal transition. PLoS ONE 7, e35440 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Gregory, P. A. et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nature Cell Biol. 10, 593–601 (2008). miR-200 and miR-205 microRNAs are shown to repress ZEB1 and ZEB2 expression. They have a crucial role in the progression of EMT, and are able to induce MET.

    Article  CAS  PubMed  Google Scholar 

  101. Bracken, C. P. et al. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 68, 7846–7854 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Kim, T. et al. p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J. Exp. Med. 208, 875–883 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Thuault, S. et al. HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J. Biol. Chem. 283, 33437–33446 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Watanabe, S. et al. HMGA2 maintains oncogenic RAS-induced epithelial-mesenchymal transition in human pancreatic cancer cells. Am. J. Pathol. 174, 854–868 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Qi, J. et al. MiR-365 regulates lung cancer and developmental gene thyroid transcription factor 1. Cell Cycle 11, 177–186 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ma, L. et al. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nature Cell Biol. 12, 247–256 (2010). The miRNA miR-9 represses E-cadherin expression, leading to activation of β-catenin signalling and, consequently, to VEGF expression, thus promoting angiogenesis and metastasis. The expression of this metastasis-promoting miRNA is activated by MYC, and correlates with MYCN amplification, in breast cancers.

    Article  CAS  PubMed  Google Scholar 

  107. Song, Y. et al. Inverse association between miR-194 expression and tumor invasion in gastric cancer. Ann. Surg. Oncol. 19 (Suppl. 3), S509–517 (2012).

    Article  PubMed  Google Scholar 

  108. Meng, Z. et al. miR-194 is a marker of hepatic epithelial cells and suppresses metastasis of liver cancer cells in mice. Hepatology 52, 2148–2157 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Zhou, Q. et al. TGF-β-induced MiR-491-5p expression promotes Par-3 degradation in rat proximal tubular epithelial cells. J. Biol. Chem. 285, 40019–40027 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Vetter, G. et al. miR-661 expression in SNAI1-induced epithelial to mesenchymal transition contributes to breast cancer cell invasion by targeting Nectin-1 and StarD10 messengers. Oncogene 29, 4436–4448 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kong, W. et al. MicroRNA-155 is regulated by the transforming growth factor β/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol. Cell. Biol. 28, 6773–6784 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Papadimitriou, E. et al. Differential regulation of the two RhoA-specific GEF isoforms Net1/Net1A by TGF-β and miR-24: role in epithelial-to-mesenchymal transition. Oncogene 31, 2862–2875 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Valastyan, S., Chang, A., Benaich, N., Reinhardt, F. & Weinberg, R. A. Concurrent suppression of integrin α5, radixin, and RhoA phenocopies the effects of miR-31 on metastasis. Cancer Res. 70, 5147–5154 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zheng, F. et al. The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut 61, 278–289 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Mercado-Pimentel, M. E. & Runyan, R. B. Multiple transforming growth factor-β isoforms and receptors function during epithelial-mesenchymal cell transformation in the embryonic heart. Cells Tissues Organs 185, 146–156 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Nawshad, A., LaGamba, D. & Hay, E. D. Transforming growth factor β (TGFβ) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT). Arch. Oral Biol. 49, 675–689 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Schnaper, H. W., Hayashida, T., Hubchak, S. C. & Poncelet, A. C. TGF-β signal transduction and mesangial cell fibrogenesis. Am. J. Physiol. Renal Physiol. 284, F243–252 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Gressner, A. M., Weiskirchen, R., Breitkopf, K. & Dooley, S. Roles of TGF-β in hepatic fibrosis. Front Biosci. 7, d793–807 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Willis, B. C. & Borok, Z. TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L525–534 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Med. 13, 952–961 (2007). This study illustrates the important pathological contribution of EndMT to fibrosis, and its control by TGFβ family proteins, with TGFβ promoting and BMP7 antagonizing EndMT.

    Article  CAS  PubMed  Google Scholar 

  121. Katsuno, Y., Lamouille, S. & Derynck, R. TGF-β signaling and epithelial-mesenchymal transition in cancer progression. Curr. Opin. Oncol. 25, 76–84 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Portella, G. et al. Transforming growth factor β is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion. Cell Growth Differ. 9, 393–404 (1998).

    CAS  PubMed  Google Scholar 

  123. Acloque, H., Adams, M. S., Fishwick, K., Bronner-Fraser, M. & Nieto, M. A. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J. Clin. Invest. 119, 1438–1449 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Sauka-Spengler, T. & Bronner-Fraser, M. A gene regulatory network orchestrates neural crest formation. Nature Rev. Mol. Cell Biol. 9, 557–568 (2008).

    Article  CAS  Google Scholar 

  125. Kruithof, B. P., Duim, S. N., Moerkamp, A. T. & Goumans, M. J. TGFβ and BMP signaling in cardiac cushion formation: lessons from mice and chicken. Differentiation 84, 89–102 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Klattig, J. & Englert, C. The Müllerian duct: recent insights into its development and regression. Sex. Dev. 1, 271–278 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Gordon, K. J., Kirkbride, K. C., How, T. & Blobe, G. C. Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2. Carcinogenesis 30, 238–248 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Zeisberg, M., Shah, A. A. & Kalluri, R. Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J. Biol. Chem. 280, 8094–8100 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Medici, D. et al. Conversion of vascular endothelial cells into multipotent stem-like cells. Nature Med. 16, 1400–1406 (2010). Endothelial cells are shown to convert into mesenchymal cells and acquire stem cell properties, dependent on the TGFβ family receptor ALK2. Lineage tracing suggests an endothelial cell origin of chondrocytes and osteoblasts in heterotypic ossification associated with fibrodysplasia ossificans progressiva.

    Article  CAS  PubMed  Google Scholar 

  130. Feng, X. H. & Derynck, R. Specificity and versatility in TGF-β signaling through Smads. Annu. Rev. Cell Dev. Biol. 21, 659–693 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Massagué, J. TGFβ signalling in context. Nature Rev. Mol. Cell Biol. 13, 616–630 (2012).

    Article  CAS  Google Scholar 

  132. Miyazono, K., ten Dijke, P. & Heldin, C. H. TGF-β signaling by Smad proteins. Adv. Immunol. 75, 115–157 (2000).

    Article  CAS  PubMed  Google Scholar 

  133. Valcourt, U., Kowanetz, M., Niimi, H., Heldin, C. H. & Moustakas, A. TGF-β and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol. Biol. Cell 16, 1987–2002 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lamouille, S. & Derynck, R. Cell size and invasion in TGF-β-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J. Cell Biol. 178, 437–451 (2007). This study illustrates the crucial role of AKT–mTOR signalling in EMT. mTORC1 is required for the increased cell size, cell motility and invasion that accompany EMT.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Piek, E., Moustakas, A., Kurisaki, A., Heldin, C. H. & ten Dijke, P. TGF-β type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J. Cell Sci. 112, 4557–4568 (1999).

    CAS  PubMed  Google Scholar 

  136. Deckers, M. et al. The tumor suppressor Smad4 is required for transforming growth factor β-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res. 66, 2202–2209 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Zavadil, J. & Böttinger, E. P. TGF-β and epithelial-to-mesenchymal transitions. Oncogene 24, 5764–5774 (2005).

    Article  CAS  PubMed  Google Scholar 

  138. Hoot, K. E. et al. Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression. J. Clin. Invest. 118, 2722–2732 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Ju, W. et al. Deletion of Smad2 in mouse liver reveals novel functions in hepatocyte growth and differentiation. Mol. Cell. Biol. 26, 654–667 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Yang, Y. C. et al. Hierarchical model of gene regulation by transforming growth factor β. Proc. Natl Acad. Sci. USA 100, 10269–10274 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Morita, T., Mayanagi, T. & Sobue, K. Dual roles of myocardin-related transcription factors in epithelial mesenchymal transition via slug induction and actin remodeling. J. Cell Biol. 179, 1027–1042 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Nishimura, G. et al. δEF1 mediates TGF-β signaling in vascular smooth muscle cell differentiation. Dev. Cell 11, 93–104 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Postigo, A. A. Opposing functions of ZEB proteins in the regulation of the TGFβ/BMP signaling pathway. EMBO J. 22, 2443–2452 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Thuault, S. et al. Transforming growth factor-β employs HMGA2 to elicit epithelial-mesenchymal transition. J. Cell Biol. 174, 175–183 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Zavadil, J. et al. Genetic programs of epithelial cell plasticity directed by transforming growth factor-β. Proc. Natl Acad. Sci. USA 98, 6686–6691 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Nawshad, A., Medici, D., Liu, C. C. & Hay, E. D. TGFβ3 inhibits E-cadherin gene expression in palate medial-edge epithelial cells through a Smad2-Smad4-LEF1 transcription complex. J. Cell Sci. 120, 1646–1653 (2007).

    Article  CAS  PubMed  Google Scholar 

  147. Kaimori, A. et al. Transforming growth factor-β1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. J. Biol. Chem. 282, 22089–22101 (2007).

    Article  CAS  PubMed  Google Scholar 

  148. Derynck, R. & Zhang, Y. E. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 425, 577–584 (2003).

    Article  CAS  PubMed  Google Scholar 

  149. Moustakas, A. & Heldin, C. H. Non-Smad TGF-β signals. J. Cell Sci. 118, 3573–3584 (2005).

    Article  CAS  PubMed  Google Scholar 

  150. Lamouille, S. & Derynck, R. Emergence of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin axis in transforming growth factor-β-induced epithelial-mesenchymal transition. Cells Tissues Organs 193, 8–22 (2011).

    Article  CAS  PubMed  Google Scholar 

  151. Ozdamar, B. et al. Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science 307, 1603–1609 (2005). TGFβ signalling is shown to confer a highly localized effect in epithelial cells, inducing RHOA degradation at tight junctions, thus contributing to epithelial disassembly and EMT.

    Article  CAS  PubMed  Google Scholar 

  152. Bhowmick, N. A. et al. Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol. Biol. Cell 12, 27–36 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Shen, X. et al. The activity of guanine exchange factor NET1 is essential for transforming growth factor-β-mediated stress fiber formation. J. Biol. Chem. 276, 15362–15368 (2001).

    Article  CAS  PubMed  Google Scholar 

  154. Vardouli, L., Moustakas, A. & Stournaras, C. LIM-kinase 2 and cofilin phosphorylation mediate actin cytoskeleton reorganization induced by transforming growth factor-β. J. Biol. Chem. 280, 11448–11457 (2005).

    Article  CAS  PubMed  Google Scholar 

  155. Tavares, A. L., Mercado-Pimentel, M. E., Runyan, R. B. & Kitten, G. T. TGF β-mediated RhoA expression is necessary for epithelial-mesenchymal transition in the embryonic chick heart. Dev. Dyn. 235, 1589–1598 (2006).

    Article  CAS  PubMed  Google Scholar 

  156. Tsapara, A. et al. The RhoA activator GEF-H1/Lfc is a transforming growth factor-β target gene and effector that regulates α-smooth muscle actin expression and cell migration. Mol. Biol. Cell 21, 860–870 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Bakin, A. V., Tomlinson, A. K., Bhowmick, N. A., Moses, H. L. & Arteaga, C. L. Phosphatidylinositol 3-kinase function is required for transforming growth factor β-mediated epithelial to mesenchymal transition and cell migration. J. Biol. Chem. 275, 36803–36810 (2000).

    Article  CAS  PubMed  Google Scholar 

  158. Lamouille, S., Connolly, E., Smyth, J. W., Akhurst, R. J. & Derynck, R. TGF-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J. Cell Sci. 125, 1259–1273 (2012). This study, together with reference 134, illustrates the crucial role of AKT–mTOR signalling in EMT. mTORC2 is required for the transition from the epithelial to the mesenchymal phenotype.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Julien, S. et al. Activation of NF-κB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene 26, 7445–7456 (2007).

    Article  CAS  PubMed  Google Scholar 

  160. Bachelder, R. E., Yoon, S. O., Franci, C., de Herreros, A. G. & Mercurio, A. M. Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J. Cell Biol. 168, 29–33 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Chaudhury, A. et al. TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nature Cell Biol. 12, 286–293 (2010). Uncovers a TGFβ-induced translational control mechanism that contributes to EMT. Phosphorylation of hnRNPE1 by AKT derepresses select target mRNAs, resulting in translational activation of DAB2 and ILEI, which are required for EMT.

    Article  CAS  PubMed  Google Scholar 

  162. Kang, J. S., Liu, C. & Derynck, R. New regulatory mechanisms of TGF-β receptor function. Trends Cell Biol. 19, 385–394 (2009).

    Article  CAS  PubMed  Google Scholar 

  163. Lee, M. K. et al. TGF-β activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J. 26, 3957–3967 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Yamashita, M. et al. TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-β. Mol. Cell 31, 918–924 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Sorrentino, A. et al. The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nature Cell Biol. 10, 1199–1207 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Xie, L. et al. Activation of the Erk pathway is required for TGF-β1-induced EMT in vitro. Neoplasia 6, 603–610 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Yu, L., Hébert, M. C. & Zhang, Y. E. TGF-β receptor-activated p38 MAP kinase mediates Smad-independent TGF-β responses. EMBO J. 21, 3749–3759 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Grande, M. et al. Transforming growth factor-β and epidermal growth factor synergistically stimulate epithelial to mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig thyrocytes. J. Cell Sci. 115, 4227–4236 (2002).

    Article  CAS  PubMed  Google Scholar 

  169. Uttamsingh, S. et al. Synergistic effect between EGF and TGF-β1 in inducing oncogenic properties of intestinal epithelial cells. Oncogene 27, 2626–2634 (2008).

    Article  CAS  PubMed  Google Scholar 

  170. Marchetti, A. et al. ERK5/MAPK is activated by TGFβ in hepatocytes and required for the GSK-3β-mediated Snail protein stabilization. Cell Signal 20, 2113–2118 (2008).

    Article  CAS  PubMed  Google Scholar 

  171. Sano, Y. et al. ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-β signaling. J. Biol. Chem. 274, 8949–8957 (1999).

    Article  CAS  PubMed  Google Scholar 

  172. Santibanez, J. F. JNK mediates TGF-β1-induced epithelial mesenchymal transdifferentiation of mouse transformed keratinocytes. FEBS Lett. 580, 5385–5391 (2006).

    Article  CAS  PubMed  Google Scholar 

  173. Stoker, M. & Perryman, M. An epithelial scatter factor released by embryo fibroblasts. J. Cell Sci. 77, 209–223 (1985).

    CAS  PubMed  Google Scholar 

  174. Gulhati, P. et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 71, 3246–3256 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Makrodouli, E. et al. BRAF and RAS oncogenes regulate Rho GTPase pathways to mediate migration and invasion properties in human colon cancer cells: a comparative study. Mol. Cancer 10, 118 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Doehn, U. et al. RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells. Mol. Cell 35, 511–522 (2009). Highlights a key contribution of the RAS–ERK MAPK pathway to EMT. The ERK MAPK-activated protein 90 kDa ribosomal protein S6 kinase is required for the induction of motile and invasive behaviour of epithelial and carcinoma cells following mesenchymal transition, through the induction of defined genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Valles, A. M., Boyer, B., Tarone, G. & Thiery, J. P. α2β1 integrin is required for the collagen and FGF-1 induced cell dispersion in a rat bladder carcinoma cell line. Cell Adhes. Commun. 4, 187–199 (1996).

    Article  CAS  PubMed  Google Scholar 

  178. Savagner, P., Yamada, K. M. & Thiery, J. P. The zinc-finger protein Slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. J. Cell Biol. 137, 1403–1419 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Billottet, C. et al. Modulation of several waves of gene expression during FGF-1 induced epithelial-mesenchymal transition of carcinoma cells. J. Cell Biochem. 104, 826–839 (2008).

    Article  CAS  PubMed  Google Scholar 

  180. Ciruna, B. & Rossant, J. FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev. Cell 1, 37–49 (2001).

    Article  CAS  PubMed  Google Scholar 

  181. Sun, X., Meyers, E. N., Lewandoski, M. & Martin, G. R. Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev. 13, 1834–1846 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Grotegut, S., von Schweinitz, D., Christofori, G. & Lehembre, F. Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO J. 25, 3534–3545 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Hiscox, S. & Jiang, W. G. Association of the HGF/SF receptor, c-met, with the cell-surface adhesion molecule, E-cadherin, and catenins in human tumor cells. Biochem. Biophys. Res. Commun. 261, 406–411 (1999).

    Article  CAS  PubMed  Google Scholar 

  184. Romano, L. A. & Runyan, R. B. Slug is an essential target of TGFβ2 signaling in the developing chicken heart. Dev. Biol. 223, 91–102 (2000).

    Article  CAS  PubMed  Google Scholar 

  185. Kim, H. J. et al. Constitutively active type I insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-κB and Snail. Mol. Cell. Biol. 27, 3165–3175 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Graham, T. R. et al. Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res. 68, 2479–2488 (2008).

    Article  CAS  PubMed  Google Scholar 

  187. Irie, H. Y. et al. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J. Cell Biol. 171, 1023–1034 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Canonici, A. et al. Insulin-like growth factor-I receptor, E-cadherin and αv integrin form a dynamic complex under the control of α-catenin. Int. J. Cancer 122, 572–582 (2008).

    Article  CAS  PubMed  Google Scholar 

  189. Lu, Z., Ghosh, S., Wang, Z. & Hunter, T. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of β-catenin, and enhanced tumor cell invasion. Cancer Cell 4, 499–515 (2003).

    Article  CAS  PubMed  Google Scholar 

  190. Lo, H. W. et al. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res. 67, 9066–9076 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Ahmed, N. et al. Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium. Am. J. Physiol. Cell Physiol. 290, C1532–1542 (2006).

    Article  CAS  PubMed  Google Scholar 

  192. Moody, S. E. et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8, 197–209 (2005).

    Article  CAS  PubMed  Google Scholar 

  193. Knutson, K. L. et al. Immunoediting of cancers may lead to epithelial to mesenchymal transition. J. Immunol. 177, 1526–1533 (2006).

    Article  CAS  PubMed  Google Scholar 

  194. Rangel, M. C. et al. Role of Cripto-1 during epithelial-to-mesenchymal transition in development and cancer. Am. J. Pathol. 180, 2188–2200 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Strizzi, L. et al. Epithelial mesenchymal transition is a characteristic of hyperplasias and tumors in mammary gland from MMTV-Cripto-1 transgenic mice. J. Cell. Physiol. 201, 266–276 (2004).

    Article  CAS  PubMed  Google Scholar 

  196. Morkel, M. et al. β-catenin regulates Cripto- and Wnt3-dependent gene expression programs in mouse axis and mesoderm formation. Development 130, 6283–6294 (2003).

    Article  CAS  PubMed  Google Scholar 

  197. Tao, Q. et al. Maternal Wnt11 activates the canonical wnt signaling pathway required for axis formation in Xenopus embryos. Cell 120, 857–871 (2005).

    Article  CAS  PubMed  Google Scholar 

  198. Yang, L., Lin, C. & Liu, Z. R. p68 RNA helicase mediates PDGF-induced epithelial mesenchymal transition by displacing Axin from beta-catenin. Cell 127, 139–155 (2006). In PDGF-induced EMT, tyrosine phosphorylation of the RNA helicase p68 is shown to promote the nuclear translocation of β-catenin through a WNT-independent pathway. Nuclear import of β-catenin and its cooperation with TCF/LEF transcription factors are required for EMT.

    Article  PubMed  Google Scholar 

  199. Robbins, J. R., McGuire, P. G., Wehrle-Haller, B. & Rogers, S. L. Diminished matrix metalloproteinase 2 (MMP-2) in ectomesenchyme-derived tissues of the Patch mutant mouse: regulation of MMP-2 by PDGF and effects on mesenchymal cell migration. Dev. Biol. 212, 255–263 (1999).

    Article  CAS  PubMed  Google Scholar 

  200. Wanami, L. S., Chen, H. Y., Peiro, S., Garcia de Herreros, A. & Bachelder, R. E. Vascular endothelial growth factor-A stimulates Snail expression in breast tumor cells: implications for tumor progression. Exp. Cell Res. 314, 2448–2453 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Yang, A. D. et al. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res. 66, 46–51 (2006).

    Article  CAS  PubMed  Google Scholar 

  202. Peinado, H. et al. Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J. Cell Sci. 117, 2827–2839 (2004).

    Article  CAS  PubMed  Google Scholar 

  203. Liu, P. et al. Requirement for Wnt3 in vertebrate axis formation. Nature Genet. 22, 361–365 (1999).

    Article  CAS  PubMed  Google Scholar 

  204. Popperl, H. et al. Misexpression of Wnt8C in the mouse induces an ectopic embryonic axis and causes a truncation of the anterior neuroectoderm. Development 124, 2997–3005 (1997).

    CAS  PubMed  Google Scholar 

  205. Garcia-Castro, M. I., Marcelle, C. & Bronner-Fraser, M. Ectodermal Wnt function as a neural crest inducer. Science 297, 848–851 (2002).

    CAS  PubMed  Google Scholar 

  206. Carmona-Fontaine, C. et al. Contact inhibition of locomotion in vivo controls neural crest directional migration. Nature 456, 957–961 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Brabletz, T. et al. Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc. Natl Acad. Sci. USA 98, 10356–10361 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Briscoe, J. & Therond, P. P. The mechanisms of Hedgehog signalling and its roles in development and disease. Nature Rev. Mol. Cell Biol. 14, 416–429 (2013).

    Article  CAS  Google Scholar 

  209. Monsoro-Burq, A. H. Sclerotome development and morphogenesis: when experimental embryology meets genetics. Int. J. Dev. Biol. 49, 301–308 (2005).

    Article  CAS  PubMed  Google Scholar 

  210. Li, X. et al. Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation. Oncogene 25, 609–621 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Fendrich, V. et al. Snail and Sonic Hedgehog activation in neuroendocrine tumors of the ileum. Endocr. Relat. Cancer 14, 865–874 (2007).

    Article  CAS  PubMed  Google Scholar 

  212. Hori, K., Sen, A. & Artavanis-Tsakonas, S. Notch signaling at a glance. J. Cell Sci. 126, 2135–2140 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Timmerman, L. A. et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 18, 99–115 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Niessen, K. et al. Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J. Cell Biol. 182, 315–325 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Xie, M. et al. Activation of Notch-1 enhances epithelial-mesenchymal transition in gefitinib-acquired resistant lung cancer cells. J. Cell Biochem. 113, 1501–1513 (2012).

    CAS  PubMed  Google Scholar 

  216. Imai, T. et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am. J. Pathol. 163, 1437–1447 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Luo, D., Wang, J., Li, J. & Post, M. Mouse Snail is a target gene for HIF. Mol. Cancer Res. 9, 234–245 (2011).

    Article  CAS  PubMed  Google Scholar 

  218. Sullivan, N. J. et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28, 2940–2947 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Yadav, A., Kumar, B., Datta, J., Teknos, T. N. & Kumar, P. IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol. Cancer Res. 9, 1658–1667 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Fernando, R. I., Castillo, M. D., Litzinger, M., Hamilton, D. H. & Palena, C. IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res. 71, 5296–5306 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Jing, Y., Han, Z., Zhang, S., Liu, Y. & Wei, L. Epithelial-mesenchymal transition in tumor microenvironment. Cell Biosci. 1, 29 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Heisenberg, C. P. & Solnica-Krezel, L. Back and forth between cell fate specification and movement during vertebrate gastrulation. Curr. Opin. Genet. Dev. 18, 311–316 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Wendt, M. K., Smith, J. A. & Schiemann, W. P. Transforming growth factor-β-induced epithelial-mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene 29, 6485–6498 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Yang, J., Dai, C. & Liu, Y. A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition. J. Am. Soc. Nephrol. 16, 68–78 (2005).

    Article  CAS  PubMed  Google Scholar 

  225. Aragon, E. et al. A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev. 25, 1275–1288 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Fuentealba, L. C. et al. Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell 131, 980–993 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Grego-Bessa, J., Diez, J., Timmerman, L. & de la Pompa, J. L. Notch and epithelial-mesenchyme transition in development and tumor progression: another turn of the screw. Cell Cycle 3, 718–721 (2004).

    Article  CAS  PubMed  Google Scholar 

  228. Zavadil, J., Cermak, L., Soto-Nieves, N. & Bottinger, E. P. Integration of TGF-β/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J. 23, 1155–1165 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Eastham, A. M. et al. Epithelial-mesenchymal transition events during human embryonic stem cell differentiation. Cancer Res. 67, 11254–11262 (2007).

    Article  CAS  PubMed  Google Scholar 

  230. Ullmann, U. et al. Epithelial-mesenchymal transition process in human embryonic stem cells cultured in feeder-free conditions. Mol. Hum. Reprod. 13, 21–32 (2007).

    Article  CAS  PubMed  Google Scholar 

  231. Mikkelsen, T. S. et al. Dissecting direct reprogramming through integrative genomic analysis. Nature 454, 49–55 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Esteban, M. A. et al. The mesenchymal-to-epithelial transition in somatic cell reprogramming. Curr. Opin. Genet. Dev. 22, 423–428 (2012).

    Article  CAS  PubMed  Google Scholar 

  233. Maherali, N. & Hochedlinger, K. TGFβ signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc. Curr. Biol. 19, 1718–1723 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Samavarchi-Tehrani, P. et al. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7, 64–77 (2010). Illustrates the key roles of MET and BMP signalling in the reprogramming of somatic cells towards induced pluripotency, and identifies BMP-dependent induction of select miRNAs as a key regulatory axis in the initiation of MET.

    Article  CAS  PubMed  Google Scholar 

  235. Subramanyam, D. et al. Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nature Biotech. 29, 443–448 (2011). The miR-302 and miR-372 miRNAs are shown to promote MET during reprogramming of human fibroblasts into pluripotent cells, and to inhibit TGFβ-induced EMT of human keratinocytes, partly through inhibition of targets that promote EMT.

    Article  CAS  Google Scholar 

  236. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008). Provides the first direct link between EMT and gain of epithelial stem cell properties. Induction of EMT in normal and malignant mammary epithelial cells results in the acquisition of stem cell-like characteristics.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Scheel, C. & Weinberg, R. A. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin. Cancer Biol. 22, 396–403 (2012). This thoughtful review conceptualizes the roles of the phenotypic plasticity associated with EMT in cancer cell behaviour and cancer progression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Brabletz, T., Jung, A., Spaderna, S., Hlubek, F. & Kirchner, T. Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nature Rev. Cancer 5, 744–749 (2005).

    Article  CAS  Google Scholar 

  239. Shipitsin, M. et al. Molecular definition of breast tumor heterogeneity. Cancer Cell 11, 259–273 (2007).

    Article  CAS  PubMed  Google Scholar 

  240. Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nature Cell Biol. 12, 468–476 (2010).

    Article  CAS  PubMed  Google Scholar 

  241. Brabletz, T. et al. Nuclear overexpression of the oncoprotein β-catenin in colorectal cancer is localized predominantly at the invasion front. Pathol. Res. Pract. 194, 701–704 (1998).

    Article  CAS  PubMed  Google Scholar 

  242. Espinoza, I., Pochampally, R., Xing, F., Watabe, K. & Miele, L. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther. 6, 1249–1259 (2013).

    PubMed  PubMed Central  Google Scholar 

  243. Ma, J., Xia, J., Miele, L., Sarkar, F. H. & Wang, Z. Notch signaling pathway in pancreatic cancer progression. Pancreat. Disord. Ther. 3, (2013).

  244. Palagani, V. et al. Epithelial mesenchymal transition and pancreatic tumor initiating CD44+/EpCAM+ cells are inhibited by γ-secretase inhibitor IX. PLoS ONE 7, e46514 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Smith, A. L. et al. The miR-106b-25 cluster targets Smad7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer. Oncogene 31, 5162–5171 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Li, Z., Yang, C. S., Nakashima, K. & Rana, T. M. Small RNA-mediated regulation of iPS cell generation. EMBO J. 30, 823–834 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Medici, D. & Kalluri, R. Endothelial-mesenchymal transition and its contribution to the emergence of stem cell phenotype. Semin. Cancer Biol. 22, 379–384 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. van Meeteren, L. A. & ten Dijke, P. Regulation of endothelial cell plasticity by TGF-β. Cell Tissue Res. 347, 177–186 (2012).

    Article  CAS  PubMed  Google Scholar 

  249. von Gise, A. & Pu, W. T. Endocardial and epicardial epithelial to mesenchymal transitions in heart development and disease. Circ. Res. 110, 1628–1645 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Zeisberg, E. M., Potenta, S., Xie, L., Zeisberg, M. & Kalluri, R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67, 10123–10128 (2007). Provides evidence that endothelial conversion into mesenchymal cells substantially contributes to the generation of carcinoma-associated stromal fibroblasts.

    Article  CAS  PubMed  Google Scholar 

  251. Medici, D. & Olsen, B. R. The role of endothelial-mesenchymal transition in heterotopic ossification. J. Bone Miner. Res. 27, 1619–1622 (2012).

    Article  PubMed  Google Scholar 

  252. Kokudo, T. et al. Snail is required for TGFβ-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. J. Cell Sci. 121, 3317–3324 (2008).

    Article  CAS  PubMed  Google Scholar 

  253. Luna-Zurita, L. et al. Integration of a Notch-dependent mesenchymal gene program and BMP2-driven cell invasiveness regulates murine cardiac valve formation. J. Clin. Invest. 120, 3493–3507 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Medici, D., Potenta, S. & Kalluri, R. Transforming growth factor-β2 promotes Snail-mediated endothelial-mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling. Biochem. J. 437, 515–520 (2011).

    Article  CAS  PubMed  Google Scholar 

  255. Rivera-Feliciano, J. et al. Development of heart valves requires Gata4 expression in endothelial-derived cells. Development 133, 3607–3618 (2006).

    Article  CAS  PubMed  Google Scholar 

  256. Quaggin, S. E. & Kapus, A. Scar wars: mapping the fate of epithelial-mesenchymal-myofibroblast transition. Kidney Int. 80, 41–50 (2011).

    Article  PubMed  Google Scholar 

  257. Radisky, D. C., Kenny, P. A. & Bissell, M. J. Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J. Cell Biochem. 101, 830–839 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Qiu, P. et al. Myocardin enhances Smad3-mediated transforming growth factor-β1 signaling in a CArG box-independent manner: Smad-binding element is an important cis element for SM22alpha transcription in vivo. Circ. Res. 97, 983–991 (2005).

    Article  CAS  PubMed  Google Scholar 

  259. Mihira, H. et al. TGF-β-induced mesenchymal transition of MS-1 endothelial cells requires Smad-dependent cooperative activation of Rho signals and MRTF-A. J. Biochem. 151, 145–156 (2012).

    Article  CAS  PubMed  Google Scholar 

  260. Masszi, A. et al. Fate-determining mechanisms in epithelial-myofibroblast transition: major inhibitory role for Smad3. J. Cell Biol. 188, 383–399 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Charbonney, E. Speight, P., Masszi, A., Nakano, H. & Kapus, A. β-catenin and Smad3 regulate the activity and stability of myocardin-related transcription factor during epithelial-myofibroblast transition. Mol. Biol. Cell 22, 4472–4485 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Lim, J. & Thiery, J. P. Epithelial-mesenchymal transitions: insights from development. Development 139, 3471–3486 (2012).

    Article  CAS  PubMed  Google Scholar 

  263. Zeisberg, M. & Kalluri, R. Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am. J. Physiol. Cell Physiol. 304, C216–225 (2013).

    Article  CAS  PubMed  Google Scholar 

  264. Chaffer, C. L., Thompson, E. W. & Williams, E. D. Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs 185, 7–19 (2007).

    Article  PubMed  Google Scholar 

  265. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  266. Cheung, M. et al. The transcriptional control of trunk neural crest induction, survival, and delamination. Dev. Cell 8, 179–192 (2005).

    Article  CAS  PubMed  Google Scholar 

  267. Mani, S. A. et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc. Natl Acad. Sci. USA 104, 10069–10074 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Nilsson, J. et al. Nuclear Janus-activated kinase 2/nuclear factor 1-C2 suppresses tumorigenesis and epithelial-to-mesenchymal transition by repressing Forkhead box F1. Cancer Res. 70, 2020–2029 (2010).

    Article  CAS  PubMed  Google Scholar 

  269. Qiao, Y. et al. FOXQ1 regulates epithelial-mesenchymal transition in human cancers. Cancer Res. 71, 3076–3086 (2011).

    Article  CAS  PubMed  Google Scholar 

  270. Belguise, K., Guo, S. & Sonenshein, G. E. Activation of FOXO3a by the green tea polyphenol epigallocatechin-3-gallate induces estrogen receptor α expression reversing invasive phenotype of breast cancer cells. Cancer Res. 67, 5763–5770 (2007).

    Article  CAS  PubMed  Google Scholar 

  271. Song, Y., Washington, M. K. & Crawford, H. C. Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. Cancer Res. 70, 2115–2125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. McDonald, O. G., Wu, H., Timp, W., Doi, A. & Feinberg, A. P. Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nature Struct. Mol. Biol. 18, 867–874 (2011).

    Article  CAS  Google Scholar 

  273. Venkov, C. D. et al. A proximal activator of transcription in epithelial-mesenchymal transition. J. Clin. Invest. 117, 482–491 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Slorach, E. M., Chou, J. & Werb, Z. Zeppo1 is a novel metastasis promoter that represses E-cadherin expression and regulates p120-catenin isoform expression and localization. Genes Dev. 25, 471–484 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Ocana, O. H. et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709–724 (2012).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors apologize to their colleagues whose work could not be cited owing to space limitations. Relevant research in the laboratory of R.D. is sponsored by US National Institutes of Health grants from the National Cancer Institute. S.L. and J.X. were recipients of scientist development awards by the US American Heart Association.

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PowerPoint slides

Glossary

Apical–basal polarity

The unequal distribution of proteins and other materials between the apical side (facing the exterior) and the basal side (facing the interior) in epithelial cells.

CD44hiCD24low phenotype

The profile of the cell surface expression of two cell surface proteins, cluster of differentiation 44 (CD44) and CD24, which correlates with epithelial and carcinoma stem cell properties and behaviour.

Front–rear polarity

Unequal distribution of proteins between the front of a migrating cell, defined by the leading edge of the membrane, and the rear, where adhesion complexes disassemble. Front–rear polarity is required for directional migration.

Tight junctions

Adhesion protein complexes between adjacent epithelial or endothelial cells. Composed of integral membrane proteins, including claudins and occludin, and the cytoplasmic proteins zonula occludens 1 (ZO1), ZO2 and ZO3, which link the transmembrane proteins to the actin cytoskeleton and signalling proteins.

Adherens junctions

Form an adhesion belt between cells and provide homophilic interactions between epithelial cadherin (E-cadherin) molecules on opposing cell surfaces. The cytoplasmic proteins β-catenin and p120 catenin associate with E-cadherin and with the actin cytoskeleton through actin-associated proteins such as α-catenin.

Desmosomes

Characterized by a 'patch' that holds cells on opposing lateral cell surfaces together, using similar protein complexes to adherens junctions. Desmosomal cadherin, desmogleins and desmocollins associate with plakoglobins and plakophilins underneath the plasma membrane, and connect to intermediate filaments through desmoplakin.

Gap junctions

Protein complexes that connect neighbouring cells and enable the passage of ions and small molecules between them through hemi-channels formed by hexamers of connexin proteins. They also provide adherence.

Apical compartment

The membrane-associated compartment at the apical side of a polarized epithelial cell.

Basolateral compartment

The membrane-associated compartment of an epithelial cell combining both the lateral sides that mediate cell–cell interactions and the basal side that enables the cell to interact with the underlying basement membrane.

Cortical actin cytoskeleton

The organization of the actin bundles and associated proteins underneath the membranes of epithelial cells that mediate cell–cell and cell–extracellular matrix interactions.

Actin stress fibre

Dynamic structures of actin filaments and associated proteins that have important roles in cell motility and contractility.

Endocardial cushion

An accumulation of cells, mostly arising from endothelial cells, in the primordial heart that will give rise to the valves and septa of the heart.

Fibrodysplasia ossificans progressiva

Very rare progressive connective tissue disease resulting in the gradual ossification of fibrous tissue, either spontaneously or in response to damage. It is caused by an activating mutation in the activin receptor type 1 (ACVR1) gene that encodes the transforming growth factor-β family type I receptor activin receptor-like kinase 2 (ALK2).

Guanine nucleotide exchange factors

(GEFs). Proteins that facilitate the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

GTPase-activating proteins

(GAPs). Proteins that inactivate small GTPases by stimulating them to hydrolyse GTP into GDP.

Guanine nucleotide dissociation inhibitors

(GDIs). Cytosolic proteins that bind to prenylated RAB proteins in their inactive, GDP-bound state. They are involved in RAB GTPase delivery to, and removal from, membranes.

Coelomic epithelium

The epithelium that lines the surface of the body wall and the abdominal organs.

Sclerotome

Part of the somite in vertebrate development that gives rise to the vertebrae and much of the skull.

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Lamouille, S., Xu, J. & Derynck, R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol 15, 178–196 (2014). https://doi.org/10.1038/nrm3758

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