New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer


Epithelial–mesenchymal transition (EMT) is a cellular programme that is known to be crucial for embryogenesis, wound healing and malignant progression. During EMT, cell–cell and cell–extracellular matrix interactions are remodelled, which leads to the detachment of epithelial cells from each other and the underlying basement membrane, and a new transcriptional programme is activated to promote the mesenchymal fate. In the context of neoplasias, EMT confers on cancer cells increased tumour-initiating and metastatic potential and a greater resistance to elimination by several therapeutic regimens. In this Review, we discuss recent findings on the mechanisms and roles of EMT in normal and neoplastic tissues, and the cell-intrinsic signals that sustain expression of this programme. We also highlight how EMT gives rise to a variety of intermediate cell states between the epithelial and the mesenchymal state, which could function as cancer stem cells. In addition, we describe the contributions of the tumour microenvironment in inducing EMT and the effects of EMT on the immunobiology of carcinomas.

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Fig. 1: Outline of a typical EMT programme.
Fig. 2: Signalling pathways that activate EMT.
Fig. 3: Activation of EMT by stromal constituents of the tumour microenvironment.
Fig. 4: EMT and modulation of the immune response.


  1. 1.

    Nieto, M. A. Epithelial–mesenchymal transitions in development and disease: old views and new perspectives. Int. J. Dev. Biol. 53, 1541–1547 (2009).

    PubMed  Google Scholar 

  2. 2.

    Nieto, M. A., Huang, R. Y., Jackson, R. A. & Thiery, J. P. EMT: 2016. Cell 166, 21–45 (2016).

    CAS  Article  Google Scholar 

  3. 3.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

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

    CAS  Google Scholar 

  5. 5.

    Ye, X. et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 525, 256–260 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Krebs, A. M. et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat. Cell Biol. 19, 518–529 (2017).

    CAS  PubMed  Google Scholar 

  8. 8.

    Mani, S. A. et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Singh, A. & Settleman, J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29, 4741–4751 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Morel, A. P. et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLOS ONE 3, e2888 (2008). This study, together with reference 8, demonstrates that carcinoma cells that have undergone EMT exhibit properties of stem cells.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Tam, W. L. & Weinberg, R. A. The epigenetics of epithelial–mesenchymal plasticity in cancer. Nat. Med. 19, 1438–1449 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Shibue, T. & Weinberg, R. A. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 14, 611–629 (2017).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Kalluri, R. EMT: when epithelial cells decide to become mesenchymal-like cells. J. Clin. Invest. 119, 1417–1419 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    CAS  PubMed  Google Scholar 

  16. 16.

    Kojima, Y. et al. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc. Natl Acad. Sci. USA 107, 20009–20014 (2010).

    CAS  PubMed  Google Scholar 

  17. 17.

    Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Terry, S. et al. New insights into the role of EMT in tumor immune escape. Mol. Oncol. 11, 824–846 (2017).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Dongre, A. et al. Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res. 77, 3982–3989 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Lamouille, S., Xu, J. & Derynck, R. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178–196 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Bierie, B. et al. Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells. Proc. Natl Acad. Sci. USA 114, E2337–E2346 (2017).

    CAS  PubMed  Google Scholar 

  22. 22.

    Grande, M. T. et al. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat. Med. 21, 989–997 (2015).

    CAS  PubMed  Google Scholar 

  23. 23.

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

    CAS  PubMed  Google Scholar 

  24. 24.

    Cano, A. et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol. 2, 76–83 (2000).

    CAS  PubMed  Google Scholar 

  25. 25.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    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).

    CAS  PubMed  Google Scholar 

  27. 27.

    Yang, M. H. et al. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat. Cell Biol. 12, 982–992 (2010).

    PubMed  Google Scholar 

  28. 28.

    Aigner, K. et al. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 26, 6979–6988 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Spaderna, S. et al. The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res. 68, 537–544 (2008).

    CAS  PubMed  Google Scholar 

  30. 30.

    Miyoshi, A. et al. Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br. J. Cancer 90, 1265–1273 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Miyoshi, A. et al. Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br. J. Cancer 92, 252–258 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Greenburg, G. & Hay, E. D. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J. Cell Biol. 95, 333–339 (1982).

    CAS  PubMed  Google Scholar 

  33. 33.

    Nieto, M. A., Sargent, M. G., Wilkinson, D. G. & Cooke, J. Control of cell behavior during vertebrate development by Slug, a zinc finger gene. Science 264, 835–839 (1994).

    CAS  PubMed  Google Scholar 

  34. 34.

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

    CAS  PubMed  Google Scholar 

  35. 35.

    Oda, H., Tsukita, S. & Takeichi, M. Dynamic behavior of the cadherin-based cell-cell adhesion system during Drosophila gastrulation. Dev. Biol. 203, 435–450 (1998).

    CAS  PubMed  Google Scholar 

  36. 36.

    Schafer, G., Narasimha, M., Vogelsang, E. & Leptin, M. Cadherin switching during the formation and differentiation of the Drosophila mesoderm – implications for epithelial-to-mesenchymal transitions. J. Cell Sci. 127, 1511–1522 (2014).

    PubMed  Google Scholar 

  37. 37.

    Simoes-Costa, M. & Bronner, M. E. Establishing neural crest identity: a gene regulatory recipe. Development 142, 242–257 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Shoval, I., Ludwig, A. & Kalcheim, C. Antagonistic roles of full-length N-cadherin and its soluble BMP cleavage product in neural crest delamination. Development 134, 491–501 (2007).

    CAS  PubMed  Google Scholar 

  39. 39.

    Clay, M. R. & Halloran, M. C. Cadherin 6 promotes neural crest cell detachment via F-actin regulation and influences active Rho distribution during epithelial-to-mesenchymal transition. Development 141, 2506–2515 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    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).

    CAS  PubMed  Google Scholar 

  41. 41.

    Aybar, M. J., Nieto, M. A. & Mayor, R. Snail precedes slug in the genetic cascade required for the specification and migration of the Xenopus neural crest. Development 130, 483–494 (2003).

    CAS  PubMed  Google Scholar 

  42. 42.

    Martinez-Alvarez, C. et al. Snail family members and cell survival in physiological and pathological cleft palates. Dev. Biol. 265, 207–218 (2004).

    CAS  PubMed  Google Scholar 

  43. 43.

    Stone, R. C. et al. Epithelial–mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res. 365, 495–506 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Savagner, P. & Arnoux, V. Epithelio-mesenchymal transition and cutaneous wound healing [French]. Bull. Acad. Natl Med. 193, 1981–1991; discussion 1992 (2009).

    CAS  PubMed  Google Scholar 

  45. 45.

    Savagner, P. et al. Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J. Cell. Physiol. 202, 858–866 (2005).

    CAS  PubMed  Google Scholar 

  46. 46.

    Baumgart, E. et al. Identification and prognostic significance of an epithelial–mesenchymal transition expression profile in human bladder tumors. Clin. Cancer Res. 13, 1685–1694 (2007).

    CAS  PubMed  Google Scholar 

  47. 47.

    Gravdal, K., Halvorsen, O. J., Haukaas, S. A. & Akslen, L. A. A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin. Cancer Res. 13, 7003–7011 (2007).

    CAS  PubMed  Google Scholar 

  48. 48.

    Kahlert, C. et al. Overexpression of ZEB2 at the invasion front of colorectal cancer is an independent prognostic marker and regulates tumor invasion in vitro. Clin. Cancer Res. 17, 7654–7663 (2011).

    CAS  PubMed  Google Scholar 

  49. 49.

    Lee, T. K. et al. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin. Cancer Res. 12, 5369–5376 (2006).

    CAS  PubMed  Google Scholar 

  50. 50.

    Mahmood, M. Q., Ward, C., Muller, H. K., Sohal, S. S. & Walters, E. H. Epithelial mesenchymal transition (EMT) and non-small cell lung cancer (NSCLC): a mutual association with airway disease. Med. Oncol. 34, 45 (2017).

    PubMed  Google Scholar 

  51. 51.

    Migita, T. et al. Epithelial-mesenchymal transition promotes SOX2 and NANOG expression in bladder cancer. Lab. Invest. 97, 567–576 (2017).

    CAS  Google Scholar 

  52. 52.

    Prudkin, L. et al. Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung. Mod. Pathol. 22, 668–678 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Roth, B. et al. Employing an orthotopic model to study the role of epithelial-mesenchymal transition in bladder cancer metastasis. Oncotarget 8, 34205–34222 (2017).

    PubMed  Google Scholar 

  54. 54.

    Shioiri, M. et al. Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients. Br. J. Cancer 94, 1816–1822 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Yan, X. et al. N-Cadherin, a novel prognostic biomarker, drives malignant progression of colorectal cancer. Mol. Med. Rep. 12, 2999–3006 (2015).

    CAS  PubMed  Google Scholar 

  56. 56.

    Zhou, Z. J. et al. HNRNPAB induces epithelial-mesenchymal transition and promotes metastasis of hepatocellular carcinoma by transcriptionally activating SNAIL. Cancer Res. 74, 2750–2762 (2014).

    CAS  PubMed  Google Scholar 

  57. 57.

    Zhu, M. et al. Decreased TIP30 promotes Snail-mediated epithelial–mesenchymal transition and tumor-initiating properties in hepatocellular carcinoma. Oncogene 34, 1420–1431 (2015).

    CAS  PubMed  Google Scholar 

  58. 58.

    Blanco, M. J. et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 21, 3241–3246 (2002).

    CAS  PubMed  Google Scholar 

  59. 59.

    Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).

    CAS  PubMed  Google Scholar 

  60. 60.

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

    CAS  PubMed  Google Scholar 

  61. 61.

    Vogelstein, B. et al. Allelotype of colorectal carcinomas. Science 244, 207–211 (1989).

    CAS  PubMed  Google Scholar 

  62. 62.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Fischer, K. R. et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472–476 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Zheng, X. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Ye, X. et al. Upholding a role for EMT in breast cancer metastasis. Nature 547, E1–E3 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Aiello, N. M. et al. Upholding a role for EMT in pancreatic cancer metastasis. Nature 547, E7–E8 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    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).

    CAS  PubMed  Google Scholar 

  68. 68.

    Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725–736 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

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

    CAS  PubMed  Google Scholar 

  70. 70.

    Cheung, K. J. & Ewald, A. J. A collective route to metastasis: seeding by tumor cell clusters. Science 352, 167–169 (2016).

    CAS  PubMed  Google Scholar 

  71. 71.

    Puram, S. V. et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 171, 1611–1624.e24 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Iwadate, Y. Epithelial–mesenchymal transition in glioblastoma progression. Oncol. Lett. 11, 1615–1620 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Fidler, I. J., Gersten, D. M. & Hart, I. R. The biology of cancer invasion and metastasis. Adv. Cancer Res. 28, 149–250 (1978).

    CAS  PubMed  Google Scholar 

  74. 74.

    Obenauf, A. C. & Massague, J. Surviving at a distance: organ specific metastasis. Trends Cancer 1, 76–91 (2015).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Dressler, G. R. The cellular basis of kidney development. Annu. Rev. Cell Dev. Biol. 22, 509–529 (2006).

    CAS  PubMed  Google Scholar 

  76. 76.

    Li, B., Zheng, Y. W., Sano, Y. & Taniguchi, H. Evidence for mesenchymal–epithelial transition associated with mouse hepatic stem cell differentiation. PLOS ONE 6, e17092 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Pattabiraman, D. R. & Weinberg, R. A. Targeting the epithelial-to-mesenchymal transition: the case for differentiation-based therapy. Cold Spring Harb. Symp. Quant. Biol. 81, 11–19 (2016).

    PubMed  Google Scholar 

  78. 78.

    Schmidt, J. M. et al. Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. Cell Rep. 10, 131–139 (2015). The studies reported in references 21, 68, 69 and 78 demonstrate that partially mesenchymal cells have stem-like abilities and can readily form metastases.

    CAS  PubMed  Google Scholar 

  79. 79.

    Beerling, E. et al. Plasticity between epithelial and mesenchymal states unlinks EMT from metastasis-enhancing stem cell capacity. Cell Rep. 14, 2281–2288 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Pattabiraman, D. R. et al. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. Science 351, aad3680 (2016). This study delineates molecular players that can reverse the EMT, leading to the loss of stem-like features of carcinoma cells.

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Bierie, B. & Moses, H. L. TGF-β and cancer. Cytokine Growth Factor Rev. 17, 29–40 (2006).

    CAS  PubMed  Google Scholar 

  82. 82.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Derynck, R., Muthusamy, B. P. & Saeteurn, K. Y. Signaling pathway cooperation in TGF-β-induced epithelial-mesenchymal transition. Curr. Opin. Cell Biol. 31, 56–66 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

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

    CAS  PubMed  Google Scholar 

  85. 85.

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

    CAS  PubMed  Google Scholar 

  86. 86.

    Gressner, A. M., Weiskirchen, R., Breitkopf, K. & Dooley, S. Roles of TGF-beta in hepatic fibrosis. Front. Biosci. 7, d793–d807 (2002).

    CAS  PubMed  Google Scholar 

  87. 87.

    Willis, B. C. & Borok, Z. TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L525–L534 (2007).

    CAS  PubMed  Google Scholar 

  88. 88.

    Ramachandran, A. et al. TGF-β uses a novel mode of receptor activation to phosphorylate SMAD1/5 and induce epithelial-to-mesenchymal transition. eLife 7, e31756 (2018).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Dhasarathy, A., Phadke, D., Mav, D., Shah, R. R. & Wade, P. A. The transcription factors Snail and Slug activate the transforming growth factor-beta signaling pathway in breast cancer. PLOS ONE 6, e26514 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Gudey, S. K., Sundar, R., Heldin, C. H., Bergh, A. & Landstrom, M. Pro-invasive properties of Snail1 are regulated by sumoylation in response to TGFbeta stimulation in cancer. Oncotarget 8, 97703–97726 (2017).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Ye, X. & Weinberg, R. A. The SUMO guards for SNAIL. Oncotarget 8, 97701–97702 (2017).

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Du, D. et al. Smad3-mediated recruitment of the methyltransferase SETDB1/ESET controls Snail1 expression and epithelial-mesenchymal transition. EMBO Rep. 19, 135–155 (2017).

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Xu, L. et al. Histone deacetylase 6 inhibition counteracts the epithelial–mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis. Oncotarget 8, 88730–88750 (2017).

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Grelet, S. et al. A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression. Nat. Cell Biol. 19, 1105–1115 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Gregory, P. A. et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 10, 593–601 (2008).

    CAS  PubMed  Google Scholar 

  96. 96.

    Korpal, M. & Kang, Y. The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. RNA Biol. 5, 115–119 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Grelet, S., McShane, A., Geslain, R. & Howe, P. H. Pleiotropic roles of non-coding RNAs in TGF-β-mediated epithelial–mesenchymal transition and their functions in tumor progression. Cancers 9, 75 (2017).

    PubMed Central  Google Scholar 

  98. 98.

    Richards, E. J. et al. Long non-coding RNAs (LncRNA) regulated by transforming growth factor (TGF) beta: lncRNA-hit-mediated TGFbeta-induced epithelial to mesenchymal transition in mammary epithelia. J. Biol. Chem. 290, 6857–6867 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Schmitz, S. U., Grote, P. & Herrmann, B. G. Mechanisms of long noncoding RNA function in development and disease. Cell. Mol. Life Sci. 73, 2491–2509 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Klaus, A. & Birchmeier, W. Wnt signalling and its impact on development and cancer. Nat. Rev. Cancer 8, 387–398 (2008).

    CAS  PubMed  Google Scholar 

  101. 101.

    Zhan, T., Rindtorff, N. & Boutros, M. Wnt signaling in cancer. Oncogene 36, 1461–1473 (2017).

    CAS  PubMed  Google Scholar 

  102. 102.

    Clevers, H. Wnt/beta-catenin signaling in development and disease. Cell 127, 469–480 (2006).

    CAS  PubMed  Google Scholar 

  103. 103.

    Savagner, P. Leaving the neighborhood: molecular mechanisms involved during epithelial–mesenchymal transition. Bioessays 23, 912–923 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

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

    CAS  PubMed  Google Scholar 

  105. 105.

    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 

  106. 106.

    Arwert, E. N., Hoste, E. & Watt, F. M. Epithelial stem cells, wound healing and cancer. Nat. Rev. Cancer 12, 170–180 (2012).

    CAS  PubMed  Google Scholar 

  107. 107.

    Gonzalez, D. M. & Medici, D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci. Signal. 7, re8 (2014).

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Tammela, T. et al. A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma. Nature 545, 355–359 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    de Sousa e Melo, F. et al. A distinct role for Lgr5+  stem cells in primary and metastatic colon cancer. Nature 543, 676–680 (2017).

    Google Scholar 

  110. 110.

    Batlle, E. & Clevers, H. Cancer stem cells revisited. Nat. Med. 23, 1124–1134 (2017).

    CAS  PubMed  Google Scholar 

  111. 111.

    Balsamo, J., Arregui, C., Leung, T. & Lilien, J. The nonreceptor protein tyrosine phosphatase PTP1B binds to the cytoplasmic domain of N-cadherin and regulates the cadherin-actin linkage. J. Cell Biol. 143, 523–532 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Wu, Y. et al. Expression of Wnt3 activates Wnt/beta-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells. Mol. Cancer Res. 10, 1597–1606 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Anastas, J. N. & Moon, R. T. WNT signalling pathways as therapeutic targets in cancer. Nat. Rev. Cancer 13, 11–26 (2013).

    CAS  PubMed  Google Scholar 

  114. 114.

    Stemmer, V., de Craene, B., Berx, G. & Behrens, J. Snail promotes Wnt target gene expression and interacts with beta-catenin. Oncogene 27, 5075–5080 (2008). This study demonstrates crosstalk between the WNT and the TGFβ pathways, two different signalling cascades that can activate the EMT.

    CAS  PubMed  Google Scholar 

  115. 115.

    Gauger, K. J., Chenausky, K. L., Murray, M. E. & Schneider, S. S. SFRP1 reduction results in an increased sensitivity to TGF-beta signaling. BMC Cancer 11, 59 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Tang, Y., Liu, Z., Zhao, L., Clemens, T. L. & Cao, X. Smad7 stabilizes beta-catenin binding to E-cadherin complex and promotes cell-cell adhesion. J. Biol. Chem. 283, 23956–23963 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Hoover, L. L. & Kubalak, S. W. Holding their own: the noncanonical roles of Smad proteins. Sci. Signal. 1, pe48 (2008).

    PubMed  PubMed Central  Google Scholar 

  118. 118.

    Scheel, C. et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145, 926–940 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Dissanayake, S. K. et al. The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J. Biol. Chem. 282, 17259–17271 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Liu, J. et al. Downregulation of miR-200a induces EMT phenotypes and CSC-like signatures through targeting the beta-catenin pathway in hepatic oval cells. PLOS ONE 8, e79409 (2013).

    PubMed  PubMed Central  Google Scholar 

  121. 121.

    Su, J. et al. MicroRNA-200a suppresses the Wnt/beta-catenin signaling pathway by interacting with beta-catenin. Int. J. Oncol. 40, 1162–1170 (2012).

    CAS  PubMed  Google Scholar 

  122. 122.

    Ma, F. et al. MiR-23a promotes TGF-beta1-induced EMT and tumor metastasis in breast cancer cells by directly targeting CDH1 and activating Wnt/beta-catenin signaling. Oncotarget 8, 69538–69550 (2017).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Zhang, J. Q. et al. MicroRNA-300 promotes apoptosis and inhibits proliferation, migration, invasion and epithelial-mesenchymal transition via the Wnt/beta-catenin signaling pathway by targeting CUL4B in pancreatic cancer cells. J. Cell. Biochem. 119, 1027–1040 (2018).

    CAS  PubMed  Google Scholar 

  124. 124.

    Osborne, B. A. & Minter, L. M. Notch signalling during peripheral T cell activation and differentiation. Nat. Rev. Immunol. 7, 64–75 (2007).

    CAS  PubMed  Google Scholar 

  125. 125.

    Kopan, R. Notch: a membrane-bound transcription factor. J. Cell Sci. 115, 1095–1097 (2002).

    CAS  PubMed  Google Scholar 

  126. 126.

    Bray, S. J. Notch signalling in context. Nat. Rev. Mol. Cell Biol. 17, 722–735 (2016).

    CAS  PubMed  Google Scholar 

  127. 127.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Bao, B. et al. Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett. 307, 26–36 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Yuan, X. et al. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J. Hematol. Oncol. 7, 87 (2014).

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    Tang, Y. & Cheng, Y. S. miR-34a inhibits pancreatic cancer progression through Snail1-mediated epithelial-mesenchymal transition and the Notch signaling pathway. Sci. Rep. 7, 38232 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Natsuizaka, M. et al. Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma. Nat. Commun. 8, 1758 (2017).

    PubMed  PubMed Central  Google Scholar 

  132. 132.

    Zhang, J. et al. NUMB negatively regulates the epithelial-mesenchymal transition of triple-negative breast cancer by antagonizing Notch signaling. Oncotarget 7, 61036–61053 (2016).

    PubMed  PubMed Central  Google Scholar 

  133. 133.

    Liu, L. et al. Notch3 is important for TGF-beta-induced epithelial–mesenchymal transition in non-small cell lung cancer bone metastasis by regulating ZEB-1. Cancer Gene Ther. 21, 364–372 (2014).

    CAS  PubMed  Google Scholar 

  134. 134.

    Xing, F. et al. Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells. Oncogene 30, 4075–4086 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Saad, S., Stanners, S. R., Yong, R., Tang, O. & Pollock, C. A. Notch mediated epithelial to mesenchymal transformation is associated with increased expression of the Snail transcription factor. Int. J. Biochem. Cell Biol. 42, 1115–1122 (2010).

    CAS  PubMed  Google Scholar 

  136. 136.

    Fukusumi, T. et al. The NOTCH4-HEY1 pathway induces epithelial mesenchymal transition in head and neck squamous cell carcinoma. Clin. Cancer Res. 24, 619–633 (2017).

    PubMed  Google Scholar 

  137. 137.

    Blokzijl, A. et al. Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3. J. Cell Biol. 163, 723–728 (2003). This study delineates how the TGFβ pathway impinges on the NOTCH signalling pathway.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Morrissey, J. et al. Transforming growth factor-beta induces renal epithelial jagged-1 expression in fibrotic disease. J. Am. Soc. Nephrol. 13, 1499–1508 (2002).

    CAS  PubMed  Google Scholar 

  140. 140.

    Di Domenico, M. & Giordano, A. Signal transduction growth factors: the effective governance of transcription and cellular adhesion in cancer invasion. Oncotarget 8, 36869–36884 (2017).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Tashiro, E., Henmi, S., Odake, H., Ino, S. & Imoto, M. Involvement of the MEK/ERK pathway in EGF-induced E-cadherin down-regulation. Biochem. Biophys. Res. Commun. 477, 801–806 (2016).

    CAS  PubMed  Google Scholar 

  143. 143.

    Tian, Y. C. et al. Epidermal growth factor and transforming growth factor-beta1 enhance HK-2 cell migration through a synergistic increase of matrix metalloproteinase and sustained activation of ERK signaling pathway. Exp. Cell Res. 313, 2367–2377 (2007).

    CAS  PubMed  Google Scholar 

  144. 144.

    Uttamsingh, S. et al. Synergistic effect between EGF and TGF-beta1 in inducing oncogenic properties of intestinal epithelial cells. Oncogene 27, 2626–2634 (2008).

    CAS  PubMed  Google Scholar 

  145. 145.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Colomiere, M. et al. Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas. Br. J. Cancer 100, 134–144 (2009).

    CAS  PubMed  Google Scholar 

  147. 147.

    Kim, J., Kong, J., Chang, H., Kim, H. & Kim, A. EGF induces epithelial–mesenchymal transition through phospho-Smad2/3-Snail signaling pathway in breast cancer cells. Oncotarget 7, 85021–85032 (2016).

    PubMed  PubMed Central  Google Scholar 

  148. 148.

    Fukuda, S. et al. Reversible interconversion and maintenance of mammary epithelial cell characteristics by the ligand-regulated EGFR system. Sci. Rep. 6, 20209 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Miyazono, K., Ehata, S. & Koinuma, D. Tumor-promoting functions of transforming growth factor-beta in progression of cancer. Ups. J. Med. Sci. 117, 143–152 (2012).

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Shirakihara, T. et al. TGF-beta regulates isoform switching of FGF receptors and epithelial–mesenchymal transition. EMBO J. 30, 783–795 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Maehara, O. et al. Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma. Carcinogenesis 38, 1073–1083 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    McNiel, E. A. & Tsichlis, P. N. Analyses of publicly available genomics resources define FGF-2-expressing bladder carcinomas as EMT-prone, proliferative tumors with low mutation rates and high expression of CTLA-4, PD-1 and PD-L1. Signal Transduct. Target. Ther. 2, 16045 (2017).

    PubMed  PubMed Central  Google Scholar 

  153. 153.

    Hu, Y., Feng, X., Mintz, A., Jeffrey Petty, W. & Hsu, W. Regulation of brachyury by fibroblast growth factor receptor 1 in lung cancer. Oncotarget 7, 87124–87135 (2016).

    PubMed  PubMed Central  Google Scholar 

  154. 154.

    Qi, L. et al. FGF4 induces epithelial–mesenchymal transition by inducing store-operated calcium entry in lung adenocarcinoma. Oncotarget 7, 74015–74030 (2016).

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    Ogunwobi, O. O., Puszyk, W., Dong, H. J. & Liu, C. Epigenetic upregulation of HGF and c-Met drives metastasis in hepatocellular carcinoma. PLOS ONE 8, e63765 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Canadas, I. et al. High circulating hepatocyte growth factor levels associate with epithelial to mesenchymal transition and poor outcome in small cell lung cancer patients. Oncotarget 5, 5246–5256 (2014).

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    Sylvester, P. W. Targeting met mediated epithelial–mesenchymal transition in the treatment of breast cancer. Clin. Transl Med. 3, 30 (2014).

    PubMed  PubMed Central  Google Scholar 

  158. 158.

    Chen, Q. Y. et al. MiR-206 inhibits HGF-induced epithelial–mesenchymal transition and angiogenesis in non-small cell lung cancer via c-Met /PI3k/Akt/mTOR pathway. Oncotarget 7, 18247–18261 (2016).

    PubMed  PubMed Central  Google Scholar 

  159. 159.

    Li, Y. et al. MiR-182 inhibits the epithelial to mesenchymal transition and metastasis of lung cancer cells by targeting the Met gene. Mol. Carcinog. 57, 125–136 (2018).

    CAS  PubMed  Google Scholar 

  160. 160.

    Zhu, G. et al. PAK5-mediated E47 phosphorylation promotes epithelial–mesenchymal transition and metastasis of colon cancer. Oncogene 35, 1943–1954 (2016).

    CAS  PubMed  Google Scholar 

  161. 161.

    Tam, W. L. et al. Protein kinase C alpha is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell 24, 347–364 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Pistore, C. et al. DNA methylation variations are required for epithelial-to-mesenchymal transition induced by cancer-associated fibroblasts in prostate cancer cells. Oncogene 36, 5551–5566 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Shintani, Y. et al. IL-6 secreted from cancer-associated fibroblasts mediates chemoresistance in NSCLC by increasing epithelial–mesenchymal transition signaling. J. Thorac. Oncol. 11, 1482–1492 (2016).

    PubMed  Google Scholar 

  164. 164.

    Yu, Y. et al. Cancer-associated fibroblasts induce epithelial–mesenchymal transition of breast cancer cells through paracrine TGF-beta signalling. Br. J. Cancer 110, 724–732 (2014).

    CAS  PubMed  Google Scholar 

  165. 165.

    Zhao, L. et al. An integrated analysis identifies STAT4 as a key regulator of ovarian cancer metastasis. Oncogene 36, 3384–3396 (2017).

    CAS  PubMed  Google Scholar 

  166. 166.

    Soon, P. S. et al. Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells. Endocr. Relat. Cancer 20, 1–12 (2013).

    CAS  PubMed  Google Scholar 

  167. 167.

    Hsu, H. C. et al. Stromal fibroblasts from the interface zone of triple negative breast carcinomas induced epithelial–mesenchymal transition and its inhibition by emodin. PLOS ONE 12, e0164661 (2017).

    PubMed  PubMed Central  Google Scholar 

  168. 168.

    Goebel, L. et al. CD4+ T cells potently induce epithelial–mesenchymal-transition in premalignant and malignant pancreatic ductal epithelial cells - novel implications of CD4+ T cells in pancreatic cancer development. Oncoimmunology 4, e1000083 (2015).

    PubMed  PubMed Central  Google Scholar 

  169. 169.

    Kmieciak, M., Knutson, K. L., Dumur, C. I. & Manjili, M. H. HER-2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell-mediated anti-tumor immune responses. Eur. J. Immunol. 37, 675–685 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Santisteban, M. et al. Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res. 69, 2887–2895 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Cohen, E. N. et al. Inflammation mediated metastasis: immune induced epithelial-to-mesenchymal transition in inflammatory breast cancer cells. PLOS ONE 10, e0132710 (2015).

    PubMed  PubMed Central  Google Scholar 

  172. 172.

    Chen, Q. et al. Growth-induced stress enhances epithelial–mesenchymal transition induced by IL-6 in clear cell renal cell carcinoma via the Akt/GSK-3beta/beta-catenin signaling pathway. Oncogenesis 6, e375 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Bonde, A. K., Tischler, V., Kumar, S., Soltermann, A. & Schwendener, R. A. Intratumoral macrophages contribute to epithelial–mesenchymal transition in solid tumors. BMC Cancer 12, 35 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Fan, Q. M. et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial–mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 352, 160–168 (2014).

    CAS  PubMed  Google Scholar 

  175. 175.

    Bates, R. C. & Mercurio, A. M. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol. Biol. Cell 14, 1790–1800 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Lin, E. Y., Nguyen, A. V., Russell, R. G. & Pollard, J. W. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193, 727–740 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010). This study delineates the molecular mechanisms by which macrophages induce metastasis of carcinoma cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Su, S. et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell 25, 605–620 (2014).

    PubMed  Google Scholar 

  179. 179.

    Lu, H. et al. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat. Cell Biol. 16, 1105–1117 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Che, D. et al. Macrophages induce EMT to promote invasion of lung cancer cells through the IL-6-mediated COX-2/PGE2/beta-catenin signalling pathway. Mol. Immunol. 90, 197–210 (2017).

    CAS  PubMed  Google Scholar 

  181. 181.

    Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Sangaletti, S. et al. Mesenchymal transition of high-grade breast carcinomas depends on extracellular matrix control of myeloid suppressor cell activity. Cell Rep. 17, 233–248 (2016).

    CAS  PubMed  Google Scholar 

  183. 183.

    Toh, B. et al. Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLOS Biol. 9, e1001162 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Ouzounova, M. et al. Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade. Nat. Commun. 8, 14979 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Ruffell, B. et al. Leukocyte composition of human breast cancer. Proc. Natl Acad. Sci. USA 109, 2796–2801 (2012).

    CAS  PubMed  Google Scholar 

  186. 186.

    Kerkar, S. P. & Restifo, N. P. Cellular constituents of immune escape within the tumor microenvironment. Cancer Res. 72, 3125–3130 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Gajewski, T. F., Schreiber, H. & Fu, Y. X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014–1022 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188.

    Kudo-Saito, C., Shirako, H., Takeuchi, T. & Kawakami, Y. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 15, 195–206 (2009). This study shows that activation of EMT can induce the formation of immunosuppressive cells in melanomas and alter their response to checkpoint blockade therapy.

    CAS  PubMed  Google Scholar 

  189. 189.

    Akalay, I. et al. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T cell-mediated lysis. Cancer Res. 73, 2418–2427 (2013).

    CAS  PubMed  Google Scholar 

  190. 190.

    Akalay, I. et al. EMT impairs breast carcinoma cell susceptibility to CTL-mediated lysis through autophagy induction. Autophagy 9, 1104–1106 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Wrzesinski, S. H., Wan, Y. Y. & Flavell, R. A. Transforming growth factor-beta and the immune response: implications for anticancer therapy. Clin. Cancer Res. 13, 5262–5270 (2007).

    CAS  PubMed  Google Scholar 

  192. 192.

    Teicher, B. A. Transforming growth factor-beta and the immune response to malignant disease. Clin. Cancer Res. 13, 6247–6251 (2007).

    CAS  PubMed  Google Scholar 

  193. 193.

    Viel, S. et al. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci. Signal. 9, ra19 (2016).

    PubMed  Google Scholar 

  194. 194.

    Bellone, G., Aste-Amezaga, M., Trinchieri, G. & Rodeck, U. Regulation of NK cell functions by TGF-beta 1. J. Immunol. 155, 1066–1073 (1995).

    CAS  PubMed  Google Scholar 

  195. 195.

    Kudo-Saito, C., Shirako, H., Ohike, M., Tsukamoto, N. & Kawakami, Y. CCL2 is critical for immunosuppression to promote cancer metastasis. Clin. Exp. Metastasis 30, 393–405 (2013).

    CAS  PubMed  Google Scholar 

  196. 196.

    Hsu, D. S. et al. Acetylation of snail modulates the cytokinome of cancer cells to enhance the recruitment of macrophages. Cancer Cell 26, 534–548 (2014).

    CAS  PubMed  Google Scholar 

  197. 197.

    Lovisa, S. et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat. Med. 21, 998–1009 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198.

    Blum, J. S., Wearsch, P. A. & Cresswell, P. Pathways of antigen processing. Annu. Rev. Immunol. 31, 443–473 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199.

    Garcia-Lora, A., Algarra, I. & Garrido, F. MHC class I antigens, immune surveillance, and tumor immune escape. J. Cell. Physiol. 195, 346–355 (2003).

    CAS  PubMed  Google Scholar 

  200. 200.

    Fruci, D. et al. Major histocompatibility complex class i and tumour immuno-evasion: how to fool T cells and natural killer cells at one time. Curr. Oncol. 19, 39–41 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201.

    Tripathi, S. C. et al. Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome. Proc. Natl Acad. Sci. USA 113, E1555–E1564 (2016).

    CAS  PubMed  Google Scholar 

  202. 202.

    Noman, M. Z. et al. The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200. Oncoimmunology 6, e1263412 (2017).

    PubMed  PubMed Central  Google Scholar 

  203. 203.

    Chen, L. et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat. Commun. 5, 5241 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Lou, Y. et al. Epithelial–mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma. Clin. Cancer Res. 22, 3630–3642 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Celia-Terrassa, T. et al. Epithelial–mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J. Clin. Invest. 122, 1849–1868 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206.

    Chaffer, C. L. et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc. Natl Acad. Sci. USA 108, 7950–7955 (2011).

    CAS  PubMed  Google Scholar 

  207. 207.

    Chaffer, C. L., San Juan, B. P., Lim, E. & Weinberg, R. A. EMT, cell plasticity and metastasis. Cancer Metastasis Rev. 35, 645–654 (2016).

    PubMed  Google Scholar 

  208. 208.

    Lim, S. et al. SNAI1-mediated epithelial–mesenchymal transition confers chemoresistance and cellular plasticity by regulating genes involved in cell death and stem cell maintenance. PLOS ONE 8, e66558 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. 209.

    Kurrey, N. K. et al. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27, 2059–2068 (2009).

    CAS  PubMed  Google Scholar 

  210. 210.

    Bharti, R., Dey, G. & Mandal, M. Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: a snapshot of IL-6 mediated involvement. Cancer Lett. 375, 51–61 (2016).

    CAS  PubMed  Google Scholar 

  211. 211.

    Pattabiraman, D. R. & Weinberg, R. A. Tackling the cancer stem cells — what challenges do they pose? Nat. Rev. Drug Discov. 13, 497–512 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  213. 213.

    Jurmeister, S. et al. MicroRNA-200c represses migration and invasion of breast cancer cells by targeting actin-regulatory proteins FHOD1 and PPM1F. Mol. Cell. Biol. 32, 633–651 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. 214.

    Cochrane, D. R., Howe, E. N., Spoelstra, N. S. & Richer, J. K. Loss of miR-200c: a marker of aggressiveness and chemoresistance in female reproductive cancers. J. Oncol. 2010, 821717 (2010).

    PubMed  Google Scholar 

  215. 215.

    Fidler, I. J. Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res. 38, 2651–2660 (1978).

    CAS  PubMed  Google Scholar 

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The authors thank T. Shibue and A. W. Lambert for critical reading of the manuscript. The authors thank R. Lee for helping with preparation of the figures. A.D. was supported by a postdoctoral fellowship from the Ludwig Fund for Cancer Research. R.A.W. is an American Cancer Society research professor and a Daniel K. Ludwig Foundation cancer research professor. The work of the authors has been supported by grants from the US National Institutes of Health (NIH) (P01 CA080111), Breast Cancer Research Foundation, Samuel Waxman Cancer Research Foundation, Breast Cancer Alliance and the Ludwig Center for Molecular Oncology.

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Correspondence to Robert A. Weinberg.

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High-grade malignancy

A poorly differentiated cancer that is typically associated with poor prognosis and reduced overall survival.

Juxtacrine signalling

A type of signalling that requires close contact between the interacting cell types. This type of signalling is also called contact-dependent signalling.

Paracrine signalling

A type of signalling that occurs via the exchange of chemical messengers such as cytokines, chemokines or ligands between the interacting cell types over somewhat short distances.

Adaptive immune system

A branch of the immune response mounted by a subset of immune cells that can recognize specific antigens, subsequently leading to the formation of immunological memory.


A type of treatment regimen that uses the immune system to mount defensive responses to diseases such as cancer. Immunotherapies restore the effector function of cytotoxic CD8+ T cells, enabling them to eradicate foreign agents.


Epithelial cell-specific intermediate filaments that are involved in desmosome stabilization to ensure the resilience of epithelial cell layers to various physical stresses.

Actin stress fibres

Contractile bundles of actin found in non-muscle cells that play important roles in morphogenesis, cell adhesion and migration.

Neural crest

A transient embryonic structure that arises in the neural tube. Neural crest cells are migratory and can differentiate into several cell types.

Regulatory T cells

(Treg cells). A subset of T cells that regulate the immune response by maintaining tolerance to self-antigens. Treg cells suppress effector T cells and are crucial for preventing autoimmunity. They are prevalent in the tumour microenvironment of most cancers.

M2 macrophages

Alternatively activated macrophages documented to secrete immunosuppressive, angiogenic and chemotactic factors. They are anti-inflammatory and promote wound healing, tissue repair and carcinoma progression.

Immunological synapse

A cellular interface formed between an antigen-presenting cell and a target cell.

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Dongre, A., Weinberg, R.A. New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol 20, 69–84 (2019).

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