Tumor Niche Disruption and Metastasis: The Role of Epithelial-Mesenchymal Transition (EMT)

  • Rita ZilhãoEmail author
  • Hélia Neves
Part of the Learning Materials in Biosciences book series (LMB)


In this chapter you will learn that, besides the initial oncogenic mutations that trigger tumorigenesis, cancer cells must have additional molecular changes and morphological modifications in order to metastasize and become malignant. One of the mechanisms that tumor cells may undergo to achieve this state is the Epithelial-Mesenchymal Transition (EMT). After giving a global perspective of what EMT is and of the main EMT activating factors, the particularities of EMT in tumors and the molecular mechanisms that underlie the tumor EMT phenotypic plasticity are adressed. Finally, the contribution of EMT studies for the development of a new generation of cancer therapies is discussed.


  1. 1.
    Gupta GP, Massagué J (2006) Cancer metastasis: building a framework. Cell 127(4):679–695. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Nguyen DX, Bos PD, Massagué J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9:274–284. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147(2):275–292. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Huber MA, Kraut N, Beug H (2005) Molecular requirements for epithelial–mesenchymal transition during tumor progression. Curr Opin Cell Biol 17(5):548–558. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Meng F, Wu G (2012) The rejuvenated scenario of epithelial--mesenchymal transition (EMT) and cancer metastasis. Cancer Metastasis Rev 31(3):455–467. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Mayor R, Carmona-Fontaine C (2010) Keeping in touch with contact inhibition of locomotion. Trends Cell Biol 20(6):319–328. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572. CrossRefPubMedGoogle Scholar
  8. 8.
    Micalizzi DS, Farabaugh SM, Ford HL (2010) Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia 15(2):117–134. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. CrossRefGoogle Scholar
  10. 10.
    Powell DR, Blasky AJ, Britt SG, Artinger KB (2013) Riding the crest of the wave: parallels between the neural crest and cancer in epithelial-to-mesenchymal transition and migration. Wiley Interdiscip Rev Syst Biol Med 5(4):511–522. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Chaffer CL, Thompson EW, Williams ED (2007) Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs 185(1–3):7–19. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559 LP–1551564. CrossRefGoogle Scholar
  13. 13.
    Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454. CrossRefPubMedGoogle Scholar
  14. 14.
    Hay ED (1968) Organization and fine structure of epithelium and mesenchyme in the developing chick embryo. In: Fleischmajer R, Billingham RE (eds) Epithel. Baltimore, MD, USA, Williams & Wilkins CoGoogle Scholar
  15. 15.
    Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial-mesenchymal transition. Natl Rev Mol Cell Biol 15(3):178–196. CrossRefGoogle Scholar
  16. 16.
    Nieto MA (2013) Epithelial plasticity: a common theme in embryonic and cancer cells. Science 342:6159. CrossRefGoogle Scholar
  17. 17.
    Qin Y, Capaldo C, Gumbiner BM, Macara IG (2005) The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J Cell Biol 171(6):1061 LP–1061071. CrossRefGoogle Scholar
  18. 18.
    Whiteman EL, Liu C-J, Fearon ER, Margolis B (2008) The transcription factor snail represses Crumbs3 expression and disrupts apico-basal polarity complexes. Oncogene 27:3875–3879. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Huang RY-J, Guilford P, Thiery JP (2012) Early events in cell adhesion and polarity during epithelial-mesenchymal transition. J Cell Sci 125(19):4417 LP–4414422. CrossRefGoogle Scholar
  20. 20.
    Kalluri R, Weinberg RA (2009) Review series The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142. CrossRefPubMedGoogle Scholar
  22. 22.
    Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR (2008) Cadherin switching. J Cell Sci 121(6):727 LP–727735. CrossRefGoogle Scholar
  23. 23.
    Beaty BT, Condeelis J (2014) Digging a little deeper: The stages of invadopodium formation and maturation. Eur J Cell Biol 93(10–12):438–444. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Leong HS, Robertson AE, Stoletov K et al (2014) Invadopodia are required for cancer cell extravasation and are a therapeutic target for metastasis. Cell Rep 8(5):1558–1570. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Nistico P, Bissell MJ, Radisky DC (2012) Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. Cold Spring Harb Perspect Biol 4(2):a011908–a011908. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lee JM, Dedhar S, Kalluri R, Thompson EW (2006) The epithelial–mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172(7):973 LP–973981. CrossRefGoogle Scholar
  27. 27.
    Kuriyama S, Mayor R (2008) Molecular analysis of neural crest migration. Philos Trans R Soc B Biol Sci 363(1495):1349 LP–1341362. CrossRefGoogle Scholar
  28. 28.
    Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA (2009) Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest 119(6):1438–1449. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Thiery JP, Acloque H, Huang RYJ, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890. CrossRefGoogle Scholar
  30. 30.
    Nieto MA, Cano A (2012) The epithelial–mesenchymal transition under control: global programs to regulate epithelial plasticity. Semin Cancer Biol 22(5–6):361–368. CrossRefGoogle Scholar
  31. 31.
    Nieto MA, Sargent MG, Wilkinson DG, Cooke J (1994) Control of cell behavior during vertebrate development by Slug, a zinc finger gene. Science 264(5160):835 LP–835839. CrossRefGoogle Scholar
  32. 32.
    Theveneau E, Mayor R (2012) Neural crest delamination and migration: from epithelium-to-mesenchyme transition to collective cell migration. Dev Biol 366(1):34–54. CrossRefGoogle Scholar
  33. 33.
    Lindsey S, Langhans SA (2014) Crosstalk of oncogenic signaling pathways during epithelial–mesenchymal transition. Front Oncol 4:358. CrossRefGoogle Scholar
  34. 34.
    Gonzalez DM, Medici D (2014) Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal 7(344):re8 LP–re8re8. CrossRefGoogle Scholar
  35. 35.
    Vincent T, Neve EPA, Johnson JR et al (2009) A SNAIL1–SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial–mesenchymal transition. Nat Cell Biol 11:943–950. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Peinado H, Quintanilla M, Cano A (2003) Transforming growth factor β-1 induces Snail transcription factor in epithelial cell lines. J Biol Chem 278(23):21113–21123. CrossRefGoogle Scholar
  37. 37.
    Yang Y, Ahn Y-H, Gibbons DL et al (2011) The Notch ligand Jagged2 promotes lung adenocarcinoma metastasis through a miR-200–dependent pathway in mice. J Clin Invest 121(4):1373–1385. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Puisieux A, Brabletz T, Caramel J (2014) Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol 16(6).
  39. 39.
    Nawshad A, Hay ED (2003) TGFβ3 signaling activates transcription of the LEF1 gene to induce epithelial mesenchymal transformation during mouse palate development. J Cell Biol 163(6):1291 LP–1291301. CrossRefGoogle Scholar
  40. 40.
    Batlle E, Sancho E, Francí C 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. CrossRefGoogle Scholar
  41. 41.
    Eger A, Aigner K, Sonderegger S et al (2005) DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 24:2375–2385. CrossRefGoogle Scholar
  42. 42.
    Yang J, Mani SA, Donaher JL et al (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–939. CrossRefGoogle Scholar
  43. 43.
    Fang X, Cai Y, Liu J et al (2011) Twist2 contributes to breast cancer progression by promoting an epithelial–mesenchymal transition and cancer stem-like cell self-renewal. Oncogene 30:4707–4720. CrossRefGoogle Scholar
  44. 44.
    Yang M-H, Hsu DS-S, Wang H-W et al (2010) Bmi1 is essential in Twist1-induced epithelial–mesenchymal transition. Nat Cell Biol 12:982–992. CrossRefPubMedGoogle Scholar
  45. 45.
    Navarro P, Lozano E, Cano A (1993) Expression of E- or P-cadherin is not sufficient to modify the morphology and the tumorigenic behavior of murine spindle carcinoma cells. Possible involvement of plakoglobin. J Cell Sci 105(4):923 LP–923934. Google Scholar
  46. 46.
    Miyoshi A, Kitajima Y, Sumi K et al (2004) Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer 90:1265–1273. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Ikenouchi J, Matsuda M, Furuse M, Tsukita S (2003) Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci 116(10):1959 LP–1951967. CrossRefGoogle Scholar
  48. 48.
    Ohkubo T, Ozawa M (2004) The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation. J Cell Sci 117(9):1675 LP–1671685. CrossRefGoogle Scholar
  49. 49.
    Zheng H, Kang Y (2013) Multilayer control of the EMT master regulators. Oncogene 33:1755–1763. CrossRefGoogle Scholar
  50. 50.
    De Craene B, Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13:97–110. CrossRefGoogle Scholar
  51. 51.
    Nakaya Y, Sheng G (2008) Epithelial to mesenchymal transition during gastrulation: An embryological view. Develop Growth Differ 50(9):755–766. CrossRefGoogle Scholar
  52. 52.
    Nakaya Y, Sheng G (2009) An amicable separation: chick’s way of doing EMT. Cell Adhes Migr 3(2):160–163. CrossRefGoogle Scholar
  53. 53.
    Hardy KM, Yatskievych TA, Konieczka JH, Bobbs AS, Antin PB (2011) FGF signalling through RAS/MAPK and PI3K pathways regulates cell movement and gene expression in the chicken primitive streak without affecting E-cadherin expression. BMC Dev Biol 11(1):20. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Ferrer-Vaquer A, Viotti M, Hadjantonakis A-K (2010) Transitions between epithelial and mesenchymal states and the morphogenesis of the early mouse embryo. Cell Adhes Migr 4(3):447–457. CrossRefGoogle Scholar
  55. 55.
    Le Douarin NM, Dupin E (2018) The “beginnings” of the neural crest. Dev Biol.
  56. 56.
    Nakaya Y, Sheng G (2013) EMT in developmental morphogenesis. Cancer Lett 341(1):9–15. CrossRefGoogle Scholar
  57. 57.
    López-Nouoa JM, Nieto MA (2009) Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med 1(6–7):303–314. CrossRefGoogle Scholar
  58. 58.
    Savagner P (2001) Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. BioEssays 23(10):912–923. CrossRefGoogle Scholar
  59. 59.
    Savagner P, Kusewitt DF, Carver EA et al (2004) Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J Cell Physiol 202(3):858–866. CrossRefGoogle Scholar
  60. 60.
    Shirley SH, Hudson LG, He J, Kusewitt DF (2010) The skinny on slug. Mol Carcinog 49(10):851–861. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Desmoulière A, Redard M, Darby I, Gabbiani G (1995) Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 146(1):56–66. PubMedPubMedCentralGoogle Scholar
  62. 62.
    Klingberg F, Hinz B, White ES (2013) The myofibroblast matrix: implications for tissue repair and fibrosis. J Pathol 229(2):298–309. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Fisher R, Pusztai L, Swanton C (2013) Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer 108:479–485. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    McGranahan N, Swanton C (2017) Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168(4):613–628. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Huang RY-J, Wong MK, Tan TZ et al (2013) An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530). Cell Death Dis 4:e915. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Nieto MA, Huang RYYJ, Jackson RAA, Thiery JPP (2016) Emt: 2016. Cell 166(1):21–45. CrossRefPubMedGoogle Scholar
  67. 67.
    Cano A, Pérez-Moreno MA, Rodrigo I et al (2000) The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2:76–83. CrossRefGoogle Scholar
  68. 68.
    Tam WL, Weinberg RA (2013) The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 19(11):1438–1449. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14(6):818–829. CrossRefGoogle Scholar
  70. 70.
    Biddle A, Liang X, Gammon L et al (2011) Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res 71(15):5317 LP–5315326. CrossRefGoogle Scholar
  71. 71.
    Roesch A, Fukunaga-Kalabis M, Schmidt EC et al (2010) A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141(4):583–594. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    O’Brien-Ball C, Biddle A (2017) Reprogramming to developmental plasticity in cancer stem cells. Dev Biol 430(2):266–274. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3:362–374. CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Friedl P, Locker J, Sahai E, Segall JE (2012) Classifying collective cancer cell invasion. Nat Cell Biol 14:777–783. CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Cheung KJ, Ewald AJ (2016) A collective route to metastasis: seeding by tumor cell clusters. Science 352(6282).
  76. 76.
    Balkwill FR, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125(23):5591 LP–5595596. CrossRefGoogle Scholar
  77. 77.
    Chang Q, Bournazou E, Sansone P et al (2013) The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia 15(7):848–862. CrossRefGoogle Scholar
  78. 78.
    Robinson BD, Sica GL, Liu Y-F et al (2009) Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res 15(7):2433 LP–2432441. CrossRefGoogle Scholar
  79. 79.
    Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1):52–67. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Chatterjee S, Seifried L, Feigin ME et al (2012) Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells. Schneider-Stock R, ed. PLoS One 7(4):e34343. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Hu X, Li D, Zhang W, Zhou J, Tang B, Li L (2012) Matrix metalloproteinase-9 expression correlates with prognosis and involved in ovarian cancer cell invasion. Arch Gynecol Obstet 286(6):1537–1543. CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Wang J, Ye C, Lu D et al (2017) Matrix metalloproteinase-1 expression in breast carcinoma: a marker for unfavorable prognosis. Oncotarget 8(53):91379–91390. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Inoue T, Yashiro M, Nishimura S, Maeda K, Sawada T, Ogawa Y, Sowa MCK (1999) Matrix metalloproteinase-1 expression is a prognostic factor for patients with advanced gastric cancer. Int J Mol Med 4(1):73–77PubMedPubMedCentralGoogle Scholar
  84. 84.
    Zucker SVJ (2004) Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer Metastasis Rev 23(1–2):101–117CrossRefGoogle Scholar
  85. 85.
    Noe V, Fingleton B, Jacobs K et al (2001) Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 114(1):111 LP–111118. Google Scholar
  86. 86.
    Paget S (1989) The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8(2):98–101PubMedPubMedCentralGoogle Scholar
  87. 87.
    Lu X, Kang Y (2007) Organotropism of breast cancer metastasis. J Mammary Gland Biol Neoplasia 12(2):153–162. CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Kaplan RN, Rafii S, Lyden D (2006) Preparing the “soil”: the premetastatic niche. Cancer Res 66(23):11089–11093. CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9(4):285–293. CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Peinado H, Alečković M, Lavotshkin S et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883–891. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Peinado H, Zhang H, Matei IR et al (2017) Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 17(5).
  92. 92.
    Hoshino A, Costa-Silva B, Shen T-L et al (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527:329–335. CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Gupta GP, Nguyen DX, Chiang AC et al (2007) Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446:765–770. CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17:1359–1370. CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Lambert AW, Pattabiraman DR, Weinberg RA (2017) Emerging biological principles of metastasis. Cell 168(4).
  96. 96.
    Brabletz T (2012) To differentiate or not–routes towards metastasis. Nat Rev Cancer 12(6):425–436. Review. PubMed PMID: 22576165
  97. 97.
    Hugo H, Ackland ML, Blick T et al (2007) Epithelial - Mesenchymal and mesenchymal - Epithelial transitions in carcinoma progression. J Cell Physiol 213(2):374–383. CrossRefGoogle Scholar
  98. 98.
    Yao D, Dai C, Peng S (2011) Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res 9(12):1608–1620. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Gao D, Joshi N, Choi H et al (2012) Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res 72(6):1384 LP–1381394. CrossRefGoogle Scholar
  100. 100.
    Chao YL, Shepard CR, Wells A (2010) Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer 9(1):179. CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Jia D, Jolly MK, Kulkarni P, Levine H (2017) Phenotypic plasticity and cell fate decisions in cancer: Insights from dynamical systems theory. Cancers (Basel). 9(7):1–19. CrossRefGoogle Scholar
  102. 102.
    Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J (2012) Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22(6):725–736. CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Beerling E, Seinstra D, de Wit E et al (2016) Plasticity between epithelial and mesenchymal states unlinks EMT from metastasis-enhancing stem cell capacity. Cell Rep 14(10).
  104. 104.
    Diepenbruck M, Christofori G (2016) Epithelial–mesenchymal transition (EMT) and metastasis: yes, no, maybe? Curr Opin Cell Biol 43:7–13. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Zheng X, Carstens JL, Kim J et al (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527(7579).
  106. 106.
    Fischer KR, Durrans A, Lee S et al (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527(7579).
  107. 107.
    Soucheray M, Capelletti M, Pulido I et al (2015) Intratumoral heterogeneity in EGFR-mutant NSCLC results in divergent resistance mechanisms in response to EGFR tyrosine kinase inhibition. Cancer Res 75(20):4372 LP–4374383. CrossRefGoogle Scholar
  108. 108.
    Baccelli I, Schneeweiss A, Riethdorf S et al (2013) Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol 31:539–544. CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Tran HD, Luitel K, Kim M, Zhang K, Longmore GD, Tran DD (2014) Transient SNAIL1 expression is necessary for metastatic competence in breast cancer. Cancer Res 74(21):6330 LP–6336340. CrossRefGoogle Scholar
  110. 110.
    Krebs AM, Mitschke J, Lasierra Losada M et al (2017) The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol 19:518–529. CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Caramel J, Papadogeorgakis E, Hill L et al (2013) A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 24(4):466–480. CrossRefPubMedGoogle Scholar
  112. 112.
    Denecker G, Vandamme N, Akay Ö et al (2014) Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression. Cell Death Differ 21:1250–1261. CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Biddle A, Mackenzie IC (2012) Cancer stem cells and EMT in carcinoma. Cancer Metastasis Rev 31(1):285–293. CrossRefGoogle Scholar
  114. 114.
    Wellner U, Brabletz T, Keck T (2010) ZEB1 in pancreatic cancer. Cancers (Basel) 2(3):1617–1628. CrossRefGoogle Scholar
  115. 115.
    Kurrey NK, Jalgaonkar SP, Joglekar AV et al (2009) 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(9):2059–2068. CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Visvader JE, Lindeman GJ (2012) Cancer stem cells: current status and evolving complexities. Cell Stem Cell 10(6):717–728. CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Lobo NA, Shimono Y, Qian D, Clarke MF (2007) The biology of cancer stem cells. Annu Rev Cell Dev Biol 23(1):675–699. CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Atena M, Reza AM, Mehran G (2014) A review on the biology of cancer stem cells. Stem Cell Discov 04(04):83–89. CrossRefGoogle Scholar
  119. 119.
    D’Andrea V, Panarese A, Tonda M, Biffoni MMM (2017) Cancer stem cells as functional biomarkers. Cancer Biomark 20(3):231–234. CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Yang M-H, Imrali A, Heeschen C (2015) Circulating cancer stem cells: the importance to select. Chin J Cancer Res 27(5):437–449. CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Kahlert UD, Joseph JV, Kruyt FAE (2017) EMT- and MET-related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities. Mol Oncol 11(7):860–877. CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Sarkar S, Horn G, Moulton K et al (2013) Cancer development, progression, and therapy: an epigenetic overview. Int J Mol Sci 14(10):21087–21113. CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Pencheva N, Tavazoie SF (2013) Control of metastatic progression by microRNA regulatory networks. Nat Cell Biol 15(6):546–554. CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Xu Q, Deng F, Qin Y et al (2016) Long non-coding RNA regulation of epithelial–mesenchymal transition in cancer metastasis. Cell Death Dis 7:e2254. CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Biamonti G, Bonomi S, Gallo S, Ghigna C (2012) Making alternative splicing decisions during epithelial-to-mesenchymal transition (EMT). Cell Mol Life Sci 69(15):2515–2526. CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Díaz VM, Viñas-Castells R, García de Herreros A (2014) Regulation of the protein stability of EMT transcription factors. Cell Adhes Migr 8(4):418–428. CrossRefGoogle Scholar
  127. 127.
    Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128(4):683–692. CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Esteller M (2008) Epigenetics in cancer. N Engl J Med 358(11):1148–1159. CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Lujambio A, Ropero S, Ballestar E et al (2007) Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res 67(4):1424 LP–1421429. CrossRefGoogle Scholar
  130. 130.
    Matsumura N, Huang Z, Mori S et al (2011) Epigenetic suppression of the TGF-beta pathway revealed by transcriptome profiling in ovarian cancer. Genome Res 21(1):74–82. CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Dong Z, Guo W, Guo Y, Kuang G, Yang Z (2012) Concordant promoter methylation of transforming growth factor-beta receptor types I and II occurs early in esophageal squamous cell carcinoma. Am J Med Sci 343(5):375–381. CrossRefGoogle Scholar
  132. 132.
    Einav Nili G-Y, Saito Y, Egger G, Jones PA (2008) Cancer epigenetics: modifications, screening, and therapy. Annu Rev Med 59(1):267–280. CrossRefGoogle Scholar
  133. 133.
    Skrypek N, Goossens S, De Smedt E, Vandamme N, Berx G (2017) Epithelial-to-mesenchymal transition: epigenetic reprogramming driving cellular plasticity. Trends Genet 33(12):943–959. CrossRefGoogle Scholar
  134. 134.
    Song SJ, Poliseno L, Song MS et al (2013) MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 154(2):311–324. CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Ma L, Teruya-Feldstein J, Weinberg RA (2007) Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449:682–688. CrossRefGoogle Scholar
  136. 136.
    He L, Thomson JM, Hemann MT et al (2005) A microRNA polycistron as a potential human oncogene. Nature 435:828–833. CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K (2010) Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol Cell 39(5):761–772. CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Olson P, Lu J, Zhang H et al (2009) MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer. Genes Dev 23(18):2152–2165. CrossRefGoogle Scholar
  139. 139.
    Breving K, Esquela-Kerscher A (2010) The complexities of microRNA regulation: mirandering around the rules. Int J Biochem Cell Biol 42(8):1316–1329. CrossRefGoogle Scholar
  140. 140.
    Jiang C, Li X, Zhao H, Liu H (2016) Long non-coding RNAs: potential new biomarkers for predicting tumor invasion and metastasis. Mol Cancer 15(1):1–15. CrossRefGoogle Scholar
  141. 141.
    Luo M, Li Z, Wang W, Zeng Y, Liu Z, Qiu J (2013) Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression. Cancer Lett 333(2):213–221. CrossRefGoogle Scholar
  142. 142.
    Takai D, Gonzales FA, Tsai YC, Thayer MJJP (2001) Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer. Hum Mol Genet 10(23):2619–2626CrossRefGoogle Scholar
  143. 143.
    Pradella D, Naro C, Sette C, Ghigna C (2017) EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression. Mol Cancer 16(1):1–19. CrossRefGoogle Scholar
  144. 144.
    Warzecha CC, Shen S, Xing Y, Carstens RP (2009) The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate diverse types of alternative splicing events. RNA Biol 6(5):546–562. CrossRefGoogle Scholar
  145. 145.
    Warzecha CC, Jiang P, Amirikian K et al (2010) An ESRP-regulated splicing programme is abrogated during the epithelial–mesenchymal transition. EMBO J 29(19):3286 LP–3283300. CrossRefGoogle Scholar
  146. 146.
    Sveen A, Kilpinen S, Ruusulehto A, Lothe RA, Skotheim RI (2015) Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes. Oncogene 35:2413. CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Pattabiraman DR, Weinberg RA (2016) Targeting the epithelial-to-mesenchymal transition: the case for differentiation-based therapy. Cold Spring Harb Symp Quant Biol 81(1).
  148. 148.
    Elaskalani O, Razak NBA, Falasca M, Metharom P (2017) Epithelial-mesenchymal transition as a therapeutic target for overcoming chemoresistance in pancreatic cancer. World J Gastrointest Oncol 9(1):37–41. CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Singh M, Yelle N, Venugopal C, Singh SK (2018) EMT: mechanisms and therapeutic implications. Pharmacol Ther 182(August 2017):80–94. CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Sarkar S, Goldgar S, Byler S, Rosenthal S, Heerboth S (2013) Demethylation and re-expression of epigenetically silenced tumor suppressor genes: sensitization of cancer cells by combination therapy. Epigenomics 5(1):87–94. CrossRefGoogle Scholar
  151. 151.
    Heerboth S, Lapinska K, Snyder N, Leary M, Rollinson S, Sarkar S (2014) Use of epigenetic drugs in disease: an overview. Genet Epigenet 6:GEG.S12270. CrossRefGoogle Scholar
  152. 152.
    Sebestyén E, Singh B, Miñana B et al (2016) Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks. Genome Res 26(6):732–744CrossRefGoogle Scholar
  153. 153.
    Bonomi S, Gallo S, Catillo M, Pignataro D, Biamonti G, Ghigna C (2013) Oncogenic alternative splicing switches: role in cancer progression and prospects for therapy. Int J Cell Biol 2013:962038. CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Kole R, Krainer AR, Altman S (2012) RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov 11:125–140. CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Rigo F, Seth PP, Bennett CF (2014) Antisense oligonucleotide-based therapies for diseases caused by pre-mRNA processing defects. In: Yeo GW (ed) Systems biology of RNA binding proteins. Springer New York, New York, NY, pp 303–352. CrossRefGoogle Scholar
  156. 156.
    McClorey G, Wood MJ (2015) An overview of the clinical application of antisense oligonucleotides for RNA-targeting therapies. Curr Opin Pharmacol 24:52–58. CrossRefGoogle Scholar
  157. 157.
    Sommers CL, Heckford SE, Skerker JM et al (1992) Loss of epithelial markers and acquisition of vimentin expression in adriamycin- and vinblastine-resistant human breast cancer cell lines. Cancer Res 52(19):5190 LP–5195197. Google Scholar
  158. 158.
    Arumugam T, Ramachandran V, Fournier KF et al (2009) Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res 69(14):5820 LP–5825828. CrossRefGoogle Scholar
  159. 159.
    McConkey DJ, Choi W, Marquis L et al (2009) Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer. Cancer Metastasis Rev 28(3):335–344. CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Wahl GM, Spike BT (2017) Cell state plasticity, stem cells, EMT, and the generation of intra-tumoral heterogeneity. npj Breast Cancer 3(1).
  161. 161.
    Hölzel M, Bovier A, Tüting T (2013) Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nat Rev Cancer 13:365–376. CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Terry S, Savagner P, Ortiz-Cuaran S et al (2017) New insights into the role of EMT in tumor immune escape. Mol Oncol 11(7).
  163. 163.
    Housman G, Byler S, Heerboth S et al (2014) Drug resistance in cancer: an overview. Cancers 6(3).
  164. 164.
    Wan L, Pantel K, Kang Y (2013) Tumor metastasis: moving new biological insights into the clinic. Nat Med 19:1450–1464. CrossRefGoogle Scholar
  165. 165.
    Brabletz T, Kalluri R, Nieto MA, Weinberg RA (2018) EMT in cancer. Nat Rev Cancer 18:128–134. CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Faculdade de Ciências da Universidade de LisboaLisbonPortugal
  2. 2.Faculdade de Medicina da Universidade de LisboaLisbonPortugal

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