Metastasis is the major cause of cancer-related deaths; therefore, the prevention and treatment of metastasis are fundamental to improving clinical outcomes. Epithelial mesenchymal transition (EMT), an evolutionarily conserved developmental program, has been implicated in carcinogenesis and confers metastatic properties upon cancer cells by enhancing mobility, invasion, and resistance to apoptotic stimuli. Furthermore, EMT-derived tumor cells acquire stem cell properties and exhibit marked therapeutic resistance. Given these attributes, the complex biological process of EMT has been heralded as a key hallmark of carcinogenesis, and targeting EMT pathways constitutes an attractive strategy for cancer treatment. However, demonstrating the necessity of EMT for metastasis in vivo has been technically challenging, and recent efforts to demonstrate a functional contribution of EMT to metastasis have yielded unexpected results. Therefore, determining the functional role of EMT in metastasis remains an area of active investigation. Studies using improved lineage tracing systems, dynamic in vivo imaging, and clinically relevant in vivo models have the potential to uncover the direct link between EMT and metastasis. This review focuses primarily on recent advances in and emerging concepts of the biology of EMT in metastasis in vivo and discusses future directions in the context of novel diagnostic and therapeutic opportunities.


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Literature Cited

  1. Mehlen P, Puisieux A. 1.  2006. Metastasis: a question of life or death. Nat. Rev. Cancer 6:449–58 [Google Scholar]
  2. Lambert AW, Pattabiraman DR, Weinberg RA. 2.  2017. Emerging biological principles of metastasis. Cell 168:670–91 [Google Scholar]
  3. Massagué J, Obenauf AC. 3.  2016. Metastatic colonization by circulating tumour cells. Nature 529:298–306 [Google Scholar]
  4. Sosa MS, Bragado P, Aguirre-Ghiso JA. 4.  2014. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat. Rev. Cancer 14:611–22 [Google Scholar]
  5. Quail DF, Joyce JA. 5.  2013. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19:1423–37 [Google Scholar]
  6. Joyce JA, Pollard JW. 6.  2009. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9:239–52 [Google Scholar]
  7. Lim J, Thiery JP. 7.  2012. Epithelial-mesenchymal transitions: insights from development. Development 139:3471–86 [Google Scholar]
  8. Kalluri R, Weinberg RA. 8.  2009. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119:1420–28 [Google Scholar]
  9. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA. 9.  et al. 2007. Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J. Cell Physiol. 213:374–83 [Google Scholar]
  10. Yang J, Weinberg RA. 10.  2008. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14:818–29 [Google Scholar]
  11. De Craene B, Berx G. 11.  2013. Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 13:97–110 [Google Scholar]
  12. Nieto MA, Huang RY, Jackson RA, Thiery JP. 12.  2016. EMT: 2016. Cell 166:21–45 [Google Scholar]
  13. Thiery JP, Acloque H, Huang RY, Nieto MA. 13.  2009. Epithelial-mesenchymal transitions in development and disease. Cell 139:871–90 [Google Scholar]
  14. Brabletz T. 14.  2012. To differentiate or not—routes towards metastasis. Nat. Rev. Cancer 12:425–36 [Google Scholar]
  15. Tam WL, Weinberg RA. 15.  2013. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat. Med. 19:1438–49 [Google Scholar]
  16. Lamouille S, Xu J, Derynck R. 16.  2014. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15:178–96 [Google Scholar]
  17. Pattabiraman DR, Weinberg RA. 17.  2017. Targeting the epithelial-to-mesenchymal transition: the case for differentiation-based therapy. Cold Spring Harb. Symp. Quant. Biol. 81:11–19 [Google Scholar]
  18. Said NA, Williams ED. 18.  2011. Growth factors in induction of epithelial-mesenchymal transition and metastasis. Cells Tissues Organs 193:85–97 [Google Scholar]
  19. Díaz-López A, Díaz-Martín J, Moreno-Bueno G, Cuevas EP, Santos V. 19.  et al. 2015. Zeb1 and Snail1 engage miR-200f transcriptional and epigenetic regulation during EMT. Int. J. Cancer 136:E62–73 [Google Scholar]
  20. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A. 20.  et al. 2008. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–15 [Google Scholar]
  21. Shibue T, Weinberg RA. 21.  2017. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 10:611–29 [Google Scholar]
  22. Diepenbruck M, Christofori G. 22.  2016. Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe?. Curr. Opin. Cell Biol. 43:7–13 [Google Scholar]
  23. Ledford H. 23.  2011. Cancer theory faces doubts. Nature 472:273 [Google Scholar]
  24. Bastid J. 24.  2012. EMT in carcinoma progression and dissemination: facts, unanswered questions, and clinical considerations. Cancer Metastasis Rev 31:277–83 [Google Scholar]
  25. Tarin D, Thompson EW, Newgreen DF. 25.  2005. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65:5996–6000 [Google Scholar]
  26. Klymkowsky MW, Savagner P. 26.  2009. Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe. Am. J. Pathol. 174:1588–93 [Google Scholar]
  27. Yu M, Bardia A, Wittner BS, Stott SL, Smas ME. 27.  et al. 2013. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339:580–84 [Google Scholar]
  28. Soini Y, Tuhkanen H, Sironen R, Virtanen I, Kataja V. 28.  et al. 2011. Transcription factors zeb1, twist and snai1 in breast carcinoma. BMC Cancer 11:73 [Google Scholar]
  29. van Nes JG, de Kruijf EM, Putter H, Faratian D, Munro A. 29.  et al. 2012. Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor-positive early breast cancer patients. Breast Cancer Res. Treat. 133:49–59 [Google Scholar]
  30. Huang RY, Guilford P, Thiery JP. 30.  2012. Early events in cell adhesion and polarity during epithelial-mesenchymal transition. J. Cell Sci. 125:4417–22 [Google Scholar]
  31. Brabletz T, Jung A, Reu S, Porzner M, Hlubek F. 31.  et al. 2001. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. PNAS 98:10356–61 [Google Scholar]
  32. Beerling E, Seinstra D, de Wit E, Kester L, van der Velden D. 32.  et al. 2016. Plasticity between epithelial and mesenchymal states unlinks EMT from metastasis-enhancing stem cell capacity. Cell Rep 14:2281–88 [Google Scholar]
  33. Fantozzi A, Gruber DC, Pisarsky L, Heck C, Kunita A. 33.  et al. 2014. VEGF-mediated angiogenesis links EMT-induced cancer stemness to tumor initiation. Cancer Res 74:1566–75 [Google Scholar]
  34. Sugino T, Yamaguchi T, Ogura G, Saito A, Hashimoto T. 34.  et al. 2004. Morphological evidence for an invasion-independent metastasis pathway exists in multiple human cancers. BMC Med 2:9 [Google Scholar]
  35. Cheung KJ, Ewald AJ. 35.  2016. A collective route to metastasis: seeding by tumor cell clusters. Science 352:167–69 [Google Scholar]
  36. Hüsemann Y, Geigl JB, Schubert F, Musiani P, Meyer M. 36.  et al. 2008. Systemic spread is an early step in breast cancer. Cancer Cell 13:58–68 [Google Scholar]
  37. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA. 37.  et al. 2004. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117:927–39 [Google Scholar]
  38. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. 38.  2012. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22:725–36 [Google Scholar]
  39. Ocaña OH, Córcoles R, Fabra A, Moreno-Bueno G, Acloque H. 39.  et al. 2012. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22:709–24 [Google Scholar]
  40. Celià-Terrassa T, Meca-Cortés O, Mateo F, Martínez de Paz A, Rubio N. 40.  et al. 2012. Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J. Clin. Invest. 122:1849–68 [Google Scholar]
  41. Tran HD, Luitel K, Kim M, Zhang K, Longmore GD, Tran DD. 41.  2014. Transient SNAIL1 expression is necessary for metastatic competence in breast cancer. Cancer Res 74:6330–40 [Google Scholar]
  42. Schmidt JM, Panzilius E, Bartsch HS, Irmler M, Beckers J. 42.  et al. 2015. Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. Cell Rep 10:131–39 [Google Scholar]
  43. Chaffer CL, Thompson EW, Williams ED. 43.  2007. Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs 185:7–19 [Google Scholar]
  44. Klein CA. 44.  2009. Parallel progression of primary tumours and metastases. Nat. Rev. Cancer 9:302–12 [Google Scholar]
  45. Hosseini H, Obradović MM, Hoffmann M, Harper KL, Sosa MS. 45.  et al. 2016. Early dissemination seeds metastasis in breast cancer. Nature 540:552–58 [Google Scholar]
  46. Harper KL, Sosa MS, Entenberg D, Hosseini H, Cheung JF. 46.  et al. 2016. Mechanism of early dissemination and metastasis in Her2+ mammary cancer. Nature 540:588–92 [Google Scholar]
  47. Reymond N, d'Água BB, Ridley AJ. 47.  2013. Crossing the endothelial barrier during metastasis. Nat. Rev. Cancer 13:858–70 [Google Scholar]
  48. Lok C. 48.  2014. Imaging: cancer caught in the act. Nature 509:148–49 [Google Scholar]
  49. Harney AS, Arwert EN, Entenberg D, Wang Y, Guo P. 49.  et al. 2015. Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov 5:932–43 [Google Scholar]
  50. Pignatelli J, Bravo-Cordero JJ, Roh-Johnson M, Gandhi SJ, Wang Y. 50.  et al. 2016. Macrophage-dependent tumor cell transendothelial migration is mediated by Notch1/Mena(INV)-initiated invadopodium formation. Sci. Rep. 6:37874 [Google Scholar]
  51. Viski C, König C, Kijewska M, Mogler C, Isacke CM, Augustin HG. 51.  2016. Endosialin-expressing pericytes promote metastatic dissemination. Cancer Res 76:5313–25 [Google Scholar]
  52. Eckert MA, Lwin TM, Chang AT, Kim J, Danis E. 52.  et al. 2011. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell 19:372–86 [Google Scholar]
  53. Eckert MA, Yang J. 53.  2011. Targeting invadopodia to block breast cancer metastasis. Oncotarget 2:562–68 [Google Scholar]
  54. Cheung KJ, Gabrielson E, Werb Z, Ewald AJ. 54.  2013. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155:1639–51 [Google Scholar]
  55. Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS. 55.  et al. 2014. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158:1110–22 [Google Scholar]
  56. Pantel K, Speicher MR. 56.  2016. The biology of circulating tumor cells. Oncogene 35:1216–24 [Google Scholar]
  57. Pantel K, Alix-Panabières C, Riethdorf S. 57.  2009. Cancer micrometastases. Nat. Rev. Clin. Oncol. 6:339–51 [Google Scholar]
  58. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J. 58.  et al. 2004. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N. Engl. J. Med. 351:781–91 [Google Scholar]
  59. Bidard FC, Peeters DJ, Fehm T, Nolé F, Gisbert-Criado R. 59.  et al. 2014. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol 15:406–14 [Google Scholar]
  60. Pantel K, Riethdorf S. 60.  2009. Pathology: Are circulating tumor cells predictive of overall survival?. Nat. Rev. Clin. Oncol. 6:190–91 [Google Scholar]
  61. Alix-Panabières C, Mader S, Pantel K. 61.  2017. Epithelial-mesenchymal plasticity in circulating tumor cells. J. Mol. Med. 95:133–42 [Google Scholar]
  62. Alix-Panabières C, Pantel K. 62.  2013. Circulating tumor cells: liquid biopsy of cancer. Clin. Chem. 59:110–18 [Google Scholar]
  63. Barriere G, Fici P, Gallerani G, Fabbri F, Zoli W, Rigaud M. 63.  2014. Circulating tumor cells and epithelial, mesenchymal and stemness markers: characterization of cell subpopulations. Ann. Transl. Med. 2:109 [Google Scholar]
  64. Khoo BL, Lee SC, Kumar P, Tan TZ, Warkiani ME. 64.  et al. 2015. Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy. Oncotarget 6:15578–93 [Google Scholar]
  65. Kasimir-Bauer S, Hoffmann O, Wallwiener D, Kimmig R, Fehm T. 65.  2012. Expression of stem cell and epithelial-mesenchymal transition markers in primary breast cancer patients with circulating tumor cells. Breast Cancer Res 14:R15 [Google Scholar]
  66. Mego M, Mani SA, Lee BN, Li C, Evans KW. 66.  et al. 2012. Expression of epithelial-mesenchymal transition-inducing transcription factors in primary breast cancer: the effect of neoadjuvant therapy. Int. J. Cancer 130:808–16 [Google Scholar]
  67. Fischer KR, Durrans A, Lee S, Sheng J, Li F. 67.  et al. 2015. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:472–76 [Google Scholar]
  68. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J. 68.  et al. 2015. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527:525–30 [Google Scholar]
  69. Labelle M, Begum S, Hynes RO. 69.  2011. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20:576–90 [Google Scholar]
  70. Mego M, Cierna Z, Janega P, Karaba M, Minarik G. 70.  et al. 2015. Relationship between circulating tumor cells and epithelial to mesenchymal transition in early breast cancer. BMC Cancer 15:533 [Google Scholar]
  71. Ni T, Li XY, Lu N, An T, Liu ZP. 71.  et al. 2016. Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer. Nat. Cell Biol. 18:1221–32 [Google Scholar]
  72. Kim NH, Kim HS, Li XY, Lee I, Choi HS. 72.  et al. 2011. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. J. Cell Biol. 195:417–33 [Google Scholar]
  73. Bonnomet A, Syne L, Brysse A, Feyereisen E, Thompson EW. 73.  et al. 2011. A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer. Oncogene 31:3741–53 [Google Scholar]
  74. Stoletov K, Kato H, Zardouzian E, Kelber J, Yang J. 74.  et al. 2010. Visualizing extravasation dynamics of metastatic tumor cells. J. Cell Sci. 123:2332–41 [Google Scholar]
  75. Shibue T, Brooks MW, Inan MF, Reinhardt F, Weinberg RA. 75.  2012. The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discov 2:706–21 [Google Scholar]
  76. Psaila B, Lyden D. 76.  2009. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9:285–93 [Google Scholar]
  77. Chambers AF, Groom AC, MacDonald IC. 77.  2002. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2:563–72 [Google Scholar]
  78. Thompson EW, Newgreen DF, Tarin D. 78.  2005. Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition?. Cancer Res 65:5991–95 [Google Scholar]
  79. Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, Williams ED. 79.  2006. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res 66:11271–78 [Google Scholar]
  80. Yates C. 80.  2011. Prostate tumor cell plasticity: a consequence of the microenvironment. Adv. Exp. Med. Biol. 720:81–90 [Google Scholar]
  81. Prudkin L, Liu DD, Ozburn NC, Sun M, Behrens C. 81.  et al. 2009. Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung. Mod. Pathol. 22:668–78 [Google Scholar]
  82. Yao D, Dai C, Peng S. 82.  2011. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol. Cancer Res. 9:1608–20 [Google Scholar]
  83. Chao YL, Shepard CR, Wells A. 83.  2010. Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol. Cancer 9:179 [Google Scholar]
  84. Brabletz T. 84.  2012. EMT and MET in metastasis: Where are the cancer stem cells?. Cancer Cell 22:699–701 [Google Scholar]
  85. Nieto MA. 85.  2013. Epithelial plasticity: a common theme in embryonic and cancer cells. Science 342:1234850 [Google Scholar]
  86. Stankic M, Pavlovic S, Chin Y, Brogi E, Padua D. 86.  et al. 2013. TGF-β-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition. Cell Rep 5:1228–42 [Google Scholar]
  87. Gao D, Joshi N, Choi H, Ryu S, Hahn M. 87.  et al. 2012. Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res 72:1384–94 [Google Scholar]
  88. Del Pozo Martin Y, Park D, Ramachandran A, Ombrato L, Calvo F. 88.  et al. 2015. Mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization. Cell Rep 13:2456–69 [Google Scholar]
  89. Tsuji T, Ibaragi S, Hu GF. 89.  2009. Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res 69:7135–39 [Google Scholar]
  90. Bill R, Christofori G. 90.  2015. The relevance of EMT in breast cancer metastasis: correlation or causality?. FEBS Lett 589:1577–87 [Google Scholar]
  91. Giampieri S, Manning C, Hooper S, Jones L, Hill CS, Sahai E. 91.  2009. Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat. Cell Biol. 11:1287–96 [Google Scholar]
  92. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM. 92.  et al. 2012. EMT and dissemination precede pancreatic tumor formation. Cell 148:349–61 [Google Scholar]
  93. Xue C, Plieth D, Venkov C, Xu C, Neilson EG. 93.  2003. The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res 63:3386–94 [Google Scholar]
  94. Trimboli AJ, Fukino K, de Bruin A, Wei G, Shen L. 94.  et al. 2008. Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res 68:937–45 [Google Scholar]
  95. Ye X, Tam WL, Shibue T, Kaygusuz Y, Reinhardt F. 95.  et al. 2015. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 525:256–60 [Google Scholar]
  96. Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E. 96.  et al. 2008. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 9:582–89 [Google Scholar]
  97. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A. 97.  et al. 2008. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 10:593–601 [Google Scholar]
  98. Korpal M, Lee ES, Hu G, Kang Y. 98.  2008. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J. Biol. Chem. 283:14910–14 [Google Scholar]
  99. Park SM, Gaur AB, Lengyel E, Peter ME. 99.  2008. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22:894–907 [Google Scholar]
  100. Zhao Z, Zhu X, Cui K, Mancuso J, Federley R. 100.  et al. 2016. In vivo visualization and characterization of epithelial-mesenchymal transition in breast tumors. Cancer Res 76:2094–104 [Google Scholar]
  101. Singh A, Settleman J. 101.  2010. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–51 [Google Scholar]
  102. Jolly MK, Boareto M, Huang B, Jia D, Lu M. 102.  et al. 2015. Implications of the hybrid epithelial/mesenchymal phenotype in metastasis. Front. Oncol. 5:155 [Google Scholar]
  103. Maheswaran S, Haber DA. 103.  2015. Cell fate: Transition loses its invasive edge. Nature 527:452–53 [Google Scholar]
  104. Li W, Kang Y. 104.  2016. Probing the fifty shades of EMT in metastasis. Trends Cancer 2:65–67 [Google Scholar]
  105. Krebs AM, Mitschke J, Lasierra Losada M, Schmalhofer O, Boerries M. 105.  et al. 2017. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat. Cell Biol. 19:518–29 [Google Scholar]
  106. Grigore AD, Jolly MK, Jia D, Farach-Carson MC, Levine H. 106.  2016. Tumor budding: The name is EMT. Partial EMT. J. Clin. Med. 5:E51 [Google Scholar]
  107. Grosse-Wilde A, Fouquier d'Hérouël A, McIntosh E, Ertaylan G, Skupin A. 107.  et al. 2015. Stemness of the hybrid epithelial/mesenchymal state in breast cancer and its association with poor survival. PLOS ONE 10:e0126522 [Google Scholar]
  108. Sampson VB, David JM, Puig I, Patil PU, de Herreros AG. 108.  et al. 2014. Wilms' tumor protein induces an epithelial-mesenchymal hybrid differentiation state in clear cell renal cell carcinoma. PLOS ONE 9:e102041 [Google Scholar]
  109. Schliekelman MJ, Taguchi A, Zhu J, Dai X, Rodriguez J. 109.  et al. 2015. Molecular portraits of epithelial, mesenchymal, and hybrid states in lung adenocarcinoma and their relevance to survival. Cancer Res 75:1789–800 [Google Scholar]
  110. Ruscetti M, Quach B, Dadashian EL, Mulholland DJ, Wu H. 110.  2015. Tracking and functional characterization of epithelial-mesenchymal transition and mesenchymal tumor cells during prostate cancer metastasis. Cancer Res 75:2749–59 [Google Scholar]
  111. Prat A, Parker JS, Karginova O, Fan C, Livasy C. 111.  et al. 2010. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12:R68 [Google Scholar]
  112. Headley MB, Bins A, Nip A, Roberts EW, Looney MR. 112.  et al. 2016. Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 531:513–17 [Google Scholar]
  113. Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert WE, Goldbrunner R. 113.  et al. 2010. Real-time imaging reveals the single steps of brain metastasis formation. Nat. Med. 16:116–22 [Google Scholar]
  114. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D. 114.  et al. 2012. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366:883–92 [Google Scholar]
  115. McGranahan N, Swanton C. 115.  2017. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168:613–28 [Google Scholar]
  116. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM. 116.  et al. 2014. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344:1396–401 [Google Scholar]
  117. Cheung KJ, Ewald AJ. 117.  2014. Illuminating breast cancer invasion: diverse roles for cell-cell interactions. Curr. Opin. Cell Biol. 30:99–111 [Google Scholar]
  118. Nieto MA. 118.  2017. Context-specific roles of EMT programmes in cancer cell dissemination. Nat. Cell Biol. 19:416–18 [Google Scholar]
  119. Tiwari N, Tiwari VK, Waldmeier L, Balwierz PJ, Arnold P. 119.  et al. 2013. Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming. Cancer Cell 23:768–83 [Google Scholar]
  120. Caramel J, Papadogeorgakis E, Hill L, Browne GJ, Richard G. 120.  et al. 2013. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 24:466–80 [Google Scholar]
  121. Denecker G, Vandamme N, Akay O, Koludrovic D, Taminau J. 121.  et al. 2014. Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression. Cell Death Differ 21:1250–61 [Google Scholar]
  122. Aparicio LA, Blanco M, Castosa R, Concha Á, Valladares M. 122.  et al. 2015. Clinical implications of epithelial cell plasticity in cancer progression. Cancer Lett 366:1–10 [Google Scholar]
  123. Davis FM, Stewart TA, Thompson EW, Monteith GR. 123.  2014. Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol. Sci. 35:479–88 [Google Scholar]
  124. Marcucci F, Stassi G, De Maria R. 124.  2016. Epithelial-mesenchymal transition: a new target in anticancer drug discovery. Nat. Rev. Drug Discov. 15:311–25 [Google Scholar]
  125. van Denderen BJ, Thompson EW. 125.  2013. Cancer: the to and fro of tumour spread. Nature 493:487–88 [Google Scholar]
  126. Voon DC, Wang H, Koo JK, Chai JH, Hor YT. 126.  et al. 2013. EMT-induced stemness and tumorigenicity are fueled by the EGFR/Ras pathway. PLOS ONE 8:e70427 [Google Scholar]
  127. Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y. 127.  2009. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 15:195–206 [Google Scholar]
  128. Terry S, Chouaib S. 128.  2015. EMT in immuno-resistance. Oncoscience 2:841–42 [Google Scholar]
  129. Rupaimoole R, Slack FJ. 129.  2017. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov. 16:203–22 [Google Scholar]
  130. Hay ED. 130.  1995. An overview of epithelio-mesenchymal transformation. Acta Anat 154:8–20 [Google Scholar]
  131. Nieto MA, Sargent MG, Wilkinson DG, Cooke J. 131.  1994. Control of cell behavior during vertebrate development by Slug, a zinc finger gene. Science 264:835–39 [Google Scholar]
  132. Greenburg G, Hay ED. 132.  1982. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J. Cell Biol. 95:333–39 [Google Scholar]
  133. Boyer B, Roche S, Denoyelle M, Thiery JP. 133.  1997. Src and Ras are involved in separate pathways in epithelial cell scattering. EMBO J 16:5904–13 [Google Scholar]
  134. Vićovac L, Aplin JD. 134.  1996. Epithelial-mesenchymal transition during trophoblast differentiation. Acta Anat 156:202–16 [Google Scholar]
  135. Batlle E, Sancho E, Francí C, Domínguez D, Monfar M. 135.  et al. 2000. The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat. Cell Biol. 2:84–89 [Google Scholar]
  136. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ. 136.  et al. 2000. The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol. 2:76–83 [Google Scholar]
  137. Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. 137.  2005. Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat. Rev. Cancer 5:744–49 [Google Scholar]
  138. Prall F. 138.  2007. Tumour budding in colorectal carcinoma. Histopathology 50:151–62 [Google Scholar]
  139. Cheung KJ, Padmanaban V, Silvestri V, Schipper K, Cohen JD. 140.  et al. 2016. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. PNAS 113:E854–63 [Google Scholar]

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