1932

Abstract

Epithelial-mesenchymal transition (EMT) is a cellular process by which epithelial cells lose their characteristics and acquire mesenchymal traits to promote cell movement. This program is aberrantly activated in human cancers and endows tumor cells with increased abilities in tumor initiation, cell migration, invasion, metastasis, and therapy resistance. The EMT program in tumors is rarely binary and often leads to a series of gradual or intermediate epithelial-mesenchymal states. Functionally, epithelial-mesenchymal plasticity (EMP) improves the fitness of cancer cells during tumor progression and in response to therapies. Here, we discuss the most recent advances in our understanding of the diverse roles of EMP in tumor initiation, progression, metastasis, and therapy resistance and address major clinical challenges due to EMP-driven phenotypic heterogeneity in cancer. Uncovering novel molecular markers and key regulators of EMP in cancer will aid the development of new therapeutic strategies to prevent cancer recurrence and overcome therapy resistance.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathmechdis-051222-122423
2024-01-24
2024-12-05
Loading full text...

Full text loading...

/deliver/fulltext/pathol/19/1/annurev-pathmechdis-051222-122423.html?itemId=/content/journals/10.1146/annurev-pathmechdis-051222-122423&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Brabletz S, Schuhwerk H, Brabletz T, Stemmler MP. 2021. Dynamic EMT: a multi-tool for tumor progression. EMBO J. 40:18e108647
    [Google Scholar]
  2. 2.
    Tsai JH, Yang J. 2013. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev 27:202192206
    [Google Scholar]
  3. 3.
    Provenzano PP, Inman DR, Eliceiri KW, Keely PJ. 2009. Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene 28:49432643
    [Google Scholar]
  4. 4.
    Wei SC, Fattet L, Tsai JH, Guo Y, Pai VH et al. 2015. Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nat. Cell Biol. 17:567888
    [Google Scholar]
  5. 5.
    Fattet L, Jung H-Y, Matsumoto MW, Aubol BE, Kumar A et al. 2020. Matrix rigidity controls epithelial-mesenchymal plasticity and tumor metastasis via a mechanoresponsive EPHA2/LYN complex. Dev. Cell 54:330216.e7
    [Google Scholar]
  6. 6.
    Nieto MA, Huang RY-J, Jackson RA, Thiery JP. 2016. EMT: 2016. Cell 166:12145
    [Google Scholar]
  7. 7.
    Dongre A, Weinberg RA. 2019. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol. 20:26984
    [Google Scholar]
  8. 8.
    Pastushenko I, Blanpain C. 2019. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 29:321226
    [Google Scholar]
  9. 9.
    Reya T, Morrison SJ, Clarke MF, Weissman IL. 2001. Stem cells, cancer, and cancer stem cells. Nature 414:685910511
    [Google Scholar]
  10. 10.
    Lytle NK, Barber AG, Reya T. 2018. Stem cell fate in cancer growth, progression and therapy resistance. Nat. Rev. Cancer 18:1166980
    [Google Scholar]
  11. 11.
    Garg M. 2022. Emerging roles of epithelial-mesenchymal plasticity in invasion-metastasis cascade and therapy resistance. Cancer Metastasis Rev 41:113145
    [Google Scholar]
  12. 12.
    Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. 2005. Migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat. Rev. Cancer 5:974449
    [Google Scholar]
  13. 13.
    Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A et al. 2008. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:470415
    [Google Scholar]
  14. 14.
    Morel A-P, Lièvre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. 2008. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLOS ONE 3:8e2888
    [Google Scholar]
  15. 15.
    Morel A-P, Hinkal GW, Thomas C, Fauvet F, Courtois-Cox S et al. 2012. EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice. PLOS Genet. 8:5e1002723
    [Google Scholar]
  16. 16.
    Ye X, Tam WL, Shibue T, Kaygusuz Y, Reinhardt F et al. 2015. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 525:756825660
    [Google Scholar]
  17. 17.
    Hojo N, Huisken AL, Wang H, Chirshev E, Kim NS et al. 2018. Snail knockdown reverses stemness and inhibits tumour growth in ovarian cancer. Sci. Rep. 8:8704
    [Google Scholar]
  18. 18.
    Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F et al. 2009. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat. Cell Biol. 11:12148795
    [Google Scholar]
  19. 19.
    Yang M-H, Hsu DS-S, Wang H-W, Wang H-J, Lan H-Y et al. 2010. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat. Cell Biol. 12:1098292
    [Google Scholar]
  20. 20.
    Hwang W-L, Jiang J-K, Yang S-H, Huang T-S, Lan H-Y et al. 2014. MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells. Nat. Cell Biol. 16:326880
    [Google Scholar]
  21. 21.
    Li H, Chen X, Calhoun-Davis T, Claypool K, Tang DG. 2008. PC3 human prostate carcinoma cell holoclones contain self-renewing tumor-initiating cells. Cancer Res. 68:6182025
    [Google Scholar]
  22. 22.
    Yoon C, Cho S-J, Chang KK, Park DJ, Ryeom SW, Yoon SS. 2017. Role of Rac1 pathway in epithelial-to-mesenchymal transition and cancer stem-like cell phenotypes in gastric adenocarcinoma. Mol. Cancer Res. 15:8110616
    [Google Scholar]
  23. 23.
    Ocaña OH, Córcoles R, Fabra Á, Moreno-Bueno G, Acloque H et al. 2012. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22:670924
    [Google Scholar]
  24. 24.
    Celià-Terrassa T, Meca-Cortés O, Mateo F, Martínez de Paz A, Rubio N et al. 2012. Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J. Clin. Investig. 122:5184968
    [Google Scholar]
  25. 25.
    Beck B, Lapouge G, Rorive S, Drogat B, Desaedelaere K et al. 2015. Different levels of Twist1 regulate skin tumor initiation, stemness, and progression. Cell Stem Cell 16:16779
    [Google Scholar]
  26. 26.
    Schmidt JM, Panzilius E, Bartsch HS, Irmler M, Beckers J et al. 2015. Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. Cell Rep. 10:213139
    [Google Scholar]
  27. 27.
    Strauss R, Li Z-Y, Liu Y, Beyer I, Persson J et al. 2011. Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity. PLOS ONE 6:1e16186
    [Google Scholar]
  28. 28.
    Goldman A, Majumder B, Dhawan A, Ravi S, Goldman D et al. 2015. Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition. Nat. Commun. 6:6139
    [Google Scholar]
  29. 29.
    Kröger C, Afeyan A, Mraz J, Eaton EN, Reinhardt F et al. 2019. Acquisition of a hybrid E/M state is essential for tumorigenicity of basal breast cancer cells. PNAS 116:15735362
    [Google Scholar]
  30. 30.
    Pastushenko I, Mauri F, Song Y, de Cock F, Meeusen B et al. 2021. Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis. Nature 589:784244855
    [Google Scholar]
  31. 31.
    Pastushenko I, Brisebarre A, Sifrim A, Fioramonti M, Revenco T et al. 2018. Identification of the tumour transition states occurring during EMT. Nature 556:770246368
    [Google Scholar]
  32. 32.
    Harner-Foreman N, Vadakekolathu J, Laversin SA, Mathieu MG, Reeder S et al. 2017. A novel spontaneous model of epithelial-mesenchymal transition (EMT) using a primary prostate cancer derived cell line demonstrating distinct stem-like characteristics. Sci. Rep. 7:40633
    [Google Scholar]
  33. 33.
    Andriani F, Bertolini G, Facchinetti F, Baldoli E, Moro M et al. 2016. Conversion to stem-cell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells. Mol. Oncol. 10:225371
    [Google Scholar]
  34. 34.
    Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E et al. 2009. Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. PNAS 106:381628186
    [Google Scholar]
  35. 35.
    Bierie B, Pierce SE, Kroeger C, Stover DG, Pattabiraman DR et al. 2017. Integrin-β4 identifies cancer stem cell–enriched populations of partially mesenchymal carcinoma cells. PNAS 114:12E233746
    [Google Scholar]
  36. 36.
    Krebs AM, Mitschke J, Lasierra Losada M, Schmalhofer O, Boerries M et al. 2017. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat. Cell Biol. 19:551829
    [Google Scholar]
  37. 37.
    Bronsert P, Kohler I, Timme S, Kiefer S, Werner M et al. 2014. Prognostic significance of zinc finger E-box binding homeobox 1 (ZEB1) expression in cancer cells and cancer-associated fibroblasts in pancreatic head cancer. Surgery 156:197108
    [Google Scholar]
  38. 38.
    Sacchetti A, Teeuwssen M, Verhagen M, Joosten R, Xu T et al. 2021. Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer. eLife 10:e61461
    [Google Scholar]
  39. 39.
    Ruscetti M, Quach B, Dadashian EL, Mulholland DJ, Wu H. 2015. Tracking and functional characterization of epithelial-mesenchymal transition and mesenchymal tumor cells during prostate cancer metastasis. Cancer Res 75:13274959
    [Google Scholar]
  40. 40.
    Liu S, Cong Y, Wang D, Sun Y, Deng L et al. 2014. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep 2:17891
    [Google Scholar]
  41. 41.
    Colacino JA, Azizi E, Brooks MD, Harouaka R, Fouladdel S et al. 2018. Heterogeneity of human breast stem and progenitor cells as revealed by transcriptional profiling. Stem Cell Rep 10:51596609
    [Google Scholar]
  42. 42.
    Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW et al. 2007. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1:331323
    [Google Scholar]
  43. 43.
    Bocci F, Gearhart-Serna L, Boareto M, Ribeiro M, Ben-Jacob E et al. 2019. Toward understanding cancer stem cell heterogeneity in the tumor microenvironment. PNAS 116:114857
    [Google Scholar]
  44. 44.
    Jolly MK, Somarelli JA, Sheth M, Biddle A, Tripathi SC et al. 2019. Hybrid epithelial/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas. Pharmacol. Ther. 194:16184
    [Google Scholar]
  45. 45.
    Quan Q, Wang X, Lu C, Ma W, Wang Y et al. 2020. Cancer stem-like cells with hybrid epithelial/mesenchymal phenotype leading the collective invasion. Cancer Sci. 111:246776
    [Google Scholar]
  46. 46.
    Cheng Y-H, Chen Y-C, Lin E, Brien R, Jung S et al. 2019. Hydro-Seq enables contamination-free high-throughput single-cell RNA-sequencing for circulating tumor cells. Nat. Commun. 10:2163
    [Google Scholar]
  47. 47.
    Papadaki MA, Stoupis G, Theodoropoulos PA, Mavroudis D, Georgoulias V, Agelaki S. 2019. Circulating tumor cells with stemness and epithelial-to-mesenchymal transition features are chemoresistant and predictive of poor outcome in metastatic breast cancer. Mol. Cancer Ther. 18:243747
    [Google Scholar]
  48. 48.
    Armstrong AJ, Marengo MS, Oltean S, Kemeny G, Bitting RL et al. 2011. Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol. Cancer Res. 9:89971007
    [Google Scholar]
  49. 49.
    Cayrefourcq L, Mazard T, Joosse S, Solassol J, Ramos J et al. 2015. Establishment and characterization of a cell line from human circulating colon cancer cells. Cancer Res. 75:5892901
    [Google Scholar]
  50. 50.
    Grillet F, Bayet E, Villeronce O, Zappia L, Lagerqvist EL et al. 2017. Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture. Gut 66:10180210
    [Google Scholar]
  51. 51.
    Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. 2003. Prospective identification of tumorigenic breast cancer cells. PNAS 100:7398388
    [Google Scholar]
  52. 52.
    Ruscetti M, Dadashian EL, Guo W, Quach B, Mulholland DJ et al. 2016. HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer. Oncogene 35:29378195
    [Google Scholar]
  53. 53.
    Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ et al. 2000. The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol. 2:27683
    [Google Scholar]
  54. 54.
    Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA et al. 2004. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117:792739
    [Google Scholar]
  55. 55.
    Thiery JP. 2002. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2:644254
    [Google Scholar]
  56. 56.
    Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, Williams ED. 2006. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor 2. Cancer Res. 66:231127178
    [Google Scholar]
  57. 57.
    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 22:672536
    [Google Scholar]
  58. 58.
    del Pozo Martin Y, Park D, Ramachandran A, Ombrato L, Calvo F et al. 2015. Mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization. Cell Rep. 13:11245669
    [Google Scholar]
  59. 59.
    Esposito M, Mondal N, Greco TM, Wei Y, Spadazzi C et al. 2019. Bone vascular niche E-selectin induces mesenchymal-epithelial transition and Wnt activation in cancer cells to promote bone metastasis. Nat. Cell Biol. 21:562739
    [Google Scholar]
  60. 60.
    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 74:21633040
    [Google Scholar]
  61. 61.
    Reichert M, Bakir B, Moreira L, Pitarresi JR, Feldmann K et al. 2018. Regulation of epithelial plasticity determines metastatic organotropism in pancreatic cancer. Dev. Cell 45:6696711.e8
    [Google Scholar]
  62. 62.
    Yang J, Antin P, Berx G, Blanpain C, Brabletz T et al. 2020. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 21:634152
    [Google Scholar]
  63. 63.
    Bornes L, Belthier G, van Rheenen J. 2021. Epithelial-to-mesenchymal transition in the light of plasticity and hybrid E/M states. J. Clin. Med. 10:112403
    [Google Scholar]
  64. 64.
    Fischer KR, Durrans A, Lee S, Sheng J, Li F et al. 2015. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:757947276
    [Google Scholar]
  65. 65.
    Park S-M, Gaur AB, Lengyel E, Peter ME. 2008. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22:7894907
    [Google Scholar]
  66. 66.
    Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A et al. 2008. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 10:5593601
    [Google Scholar]
  67. 67.
    Li Y, Lv Z, Zhang S, Wang Z, He L et al. 2020. Genetic fate mapping of transient cell fate reveals N-cadherin activity and function in tumor metastasis. Dev. Cell 54:5593607.e5
    [Google Scholar]
  68. 68.
    Ye X, Brabletz T, Kang Y, Longmore GD, Nieto MA et al. 2017. Upholding a role for EMT in breast cancer metastasis. Nature 547:7661E13
    [Google Scholar]
  69. 69.
    Lüönd F, Sugiyama N, Bill R, Bornes L, Hager C et al. 2021. Distinct contributions of partial and full EMT to breast cancer malignancy. Dev Cell 56:23320321.e11
    [Google Scholar]
  70. 70.
    Simeonov KP, Byrns CN, Clark ML, Norgard RJ, Martin B et al. 2021. Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states. Cancer Cell 39:8115062.e9
    [Google Scholar]
  71. 71.
    Aiello NM, Maddipati R, Norgard RJ, Balli D, Li J et al. 2018. EMT subtype influences epithelial plasticity and mode of cell migration. Dev. Cell 45:668195.e4
    [Google Scholar]
  72. 72.
    Zheng X, Carstens JL, Kim J, Scheible M, Kaye J et al. 2015. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527:757952530
    [Google Scholar]
  73. 73.
    Xu Y, Lee D-K, Feng Z, Xu Y, Bu W et al. 2017. Breast tumor cell-specific knockout of Twist1 inhibits cancer cell plasticity, dissemination, and lung metastasis in mice. PNAS 114:431149499
    [Google Scholar]
  74. 74.
    Friedl P, Locker J, Sahai E, Segall JE. 2012. Classifying collective cancer cell invasion. Nat. Cell Biol. 14:877783
    [Google Scholar]
  75. 75.
    Cheung KJ, Gabrielson E, Werb Z, Ewald AJ. 2013. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155:7163951
    [Google Scholar]
  76. 76.
    Campbell K, Casanova J. 2016. A common framework for EMT and collective cell migration. Development 143:234291300
    [Google Scholar]
  77. 77.
    Dang TT, Esparza MA, Maine EA, Westcott JM, Pearson GW. 2015. ΔNp63α promotes breast cancer cell motility through the selective activation of components of the epithelial-to-mesenchymal transition program. Cancer Res. 75:18392535
    [Google Scholar]
  78. 78.
    Yu M, Bardia A, Wittner BS, Stott SL, Smas ME et al. 2013. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339:611958084
    [Google Scholar]
  79. 79.
    Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS et al. 2014. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158:5111022
    [Google Scholar]
  80. 80.
    Mizukoshi K, Okazawa Y, Haeno H, Koyama Y, Sulidan K et al. 2020. Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state. Int. J. Cancer 146:9254762
    [Google Scholar]
  81. 81.
    Dillekås H, Rogers MS, Straume O. 2019. Are 90% of deaths from cancer caused by metastases?. Cancer Med 8:12557476
    [Google Scholar]
  82. 82.
    Sosa MS, Bragado P, Aguirre-Ghiso JA. 2014. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat. Rev. Cancer 14:961122
    [Google Scholar]
  83. 83.
    Blasco MT, Espuny I, Gomis RR. 2022. Ecology and evolution of dormant metastasis. Trends Cancer 8:757082
    [Google Scholar]
  84. 84.
    Massagué J, Obenauf AC. 2016. Metastatic colonization by circulating tumour cells. Nature 529:7586298306
    [Google Scholar]
  85. 85.
    Bonnomet A, Syne L, Brysse A, Feyereisen E, Thompson EW et al. 2012. A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer. Oncogene 31:33374153
    [Google Scholar]
  86. 86.
    Padmanaban V, Krol I, Suhail Y, Szczerba BM, Aceto N et al. 2019. E-cadherin is required for metastasis in multiple models of breast cancer. Nature 573:777443944
    [Google Scholar]
  87. 87.
    Vega S, Morales AV, Ocaña OH, Valdés F, Fabregat I, Nieto MA. 2004. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 18:10113143
    [Google Scholar]
  88. 88.
    Mejlvang J, Kriajevska M, Vandewalle C, Chernova T, Sayan AE et al. 2007. Direct repression of cyclin D1 by SIP1 attenuates cell cycle progression in cells undergoing an epithelial mesenchymal transition. Mol. Biol. Cell 18:11461524
    [Google Scholar]
  89. 89.
    Korpal M, Ell BJ, Buffa FM, Ibrahim T, Blanco MA et al. 2011. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat. Med. 17:911018
    [Google Scholar]
  90. 90.
    Jiang J, Zheng M, Zhang M, Yang X, Li L et al. 2019. PRRX1 regulates cellular phenotype plasticity and dormancy of head and neck squamous cell carcinoma through miR-642b-3p. Neoplasia 21:221629
    [Google Scholar]
  91. 91.
    Takano S, Reichert M, Bakir B, Das KK, Nishida T et al. 2016. Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization. Genes Dev 30:223347
    [Google Scholar]
  92. 92.
    Xu Z, Pang TCY, Liu AC, Pothula SP, Mekapogu AR et al. 2020. Targeting the HGF/c-MET pathway in advanced pancreatic cancer: a key element of treatment that limits primary tumour growth and eliminates metastasis. Br. J. Cancer 122:10148695
    [Google Scholar]
  93. 93.
    Lawson DA, Bhakta NR, Kessenbrock K, Prummel KD, Yu Y et al. 2015. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature 526:757113135
    [Google Scholar]
  94. 94.
    Harper KL, Sosa MS, Entenberg D, Hosseini H, Cheung JF et al. 2016. Mechanism of early dissemination and metastasis in Her2+ mammary cancer. Nature 540:763458892
    [Google Scholar]
  95. 95.
    Celià-Terrassa T, Bastian C, Liu DD, Ell B, Aiello NM et al. 2018. Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability. Nat. Commun. 9:5005
    [Google Scholar]
  96. 96.
    Aouad P, Zhang Y, De Martino F, Stibolt C, Ali S et al. 2022. Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence. Nat. Commun. 13:4975
    [Google Scholar]
  97. 97.
    Nobre AR, Dalla E, Yang J, Huang X, Wullkopf L et al. 2022. ZFP281 drives a mesenchymal-like dormancy program in early disseminated breast cancer cells that prevents metastatic outgrowth in the lung. Nat. Cancer 3:10116580
    [Google Scholar]
  98. 98.
    Goss PE, Chambers AF. 2010. Does tumour dormancy offer a therapeutic target?. Nat. Rev. Cancer 10:1287177
    [Google Scholar]
  99. 99.
    Bragado P, Estrada Y, Parikh F, Krause S, Capobianco C et al. 2013. TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling. Nat. Cell Biol. 15:11135161
    [Google Scholar]
  100. 100.
    Prunier C, Baker D, Ten Dijke P, Ritsma L 2019. TGF-β family signaling pathways in cellular dormancy. Trends Cancer 5:16678
    [Google Scholar]
  101. 101.
    Tyagi A, Sharma S, Wu K, Wu S-Y, Xing F et al. 2021. Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung. Nat. Commun. 12:474
    [Google Scholar]
  102. 102.
    Ju S, Wang F, Wang Y, Ju S. 2020. CSN8 is a key regulator in hypoxia-induced epithelial-mesenchymal transition and dormancy of colorectal cancer cells. Mol. Cancer 19:1168
    [Google Scholar]
  103. 103.
    Bado IL, Zhang W, Hu J, Xu Z, Wang H et al. 2021. The bone microenvironment increases phenotypic plasticity of ER+ breast cancer cells. Dev. Cell 56:8110017.e9
    [Google Scholar]
  104. 104.
    Mohd Ali N, Yeap SK, Ho WY, Boo L, Ky H et al. 2020. Adipose MSCs suppress MCF7 and MDA-MB-231 breast cancer metastasis and EMT pathways leading to dormancy via exosomal-miRNAs following co-culture interaction. Pharmaceuticals 14:18
    [Google Scholar]
  105. 105.
    Liang Y-K, Lin H-Y, Dou X-W, Chen M, Wei X-L et al. 2018. MiR-221/222 promote epithelial-mesenchymal transition by targeting Notch3 in breast cancer cell lines. npj Breast Cancer 4:20
    [Google Scholar]
  106. 106.
    Cao R, Yuan L, Ma B, Wang G, Qiu W, Tian Y. 2020. An EMT-related gene signature for the prognosis of human bladder cancer. J. Cell. Mol. Med. 24:160517
    [Google Scholar]
  107. 107.
    Zhang Z, Yu Y, Li P, Wang M, Jiao W et al. 2022. Identification and validation of an immune signature associated with EMT and metabolic reprogramming for predicting prognosis and drug response in bladder cancer. Front. Immunol. 13:954616
    [Google Scholar]
  108. 108.
    Xue W, Sun C, Yuan H, Yang X, Zhang Q et al. 2022. Establishment and analysis of an individualized EMT-related gene signature for the prognosis of breast cancer in female patients. Dis. Markers 2022:1289445
    [Google Scholar]
  109. 109.
    Tao H, Zhang Y, Yuan T, Li J, Liu J et al. 2022. Identification of an EMT-related lncRNA signature and LINC01116 as an immune-related oncogene in hepatocellular carcinoma. Aging 14:3147391
    [Google Scholar]
  110. 110.
    Yang Y, Feng M, Bai L, Liao W, Zhou K et al. 2021. Comprehensive analysis of EMT-related genes and lncRNAs in the prognosis, immunity, and drug treatment of colorectal cancer. J. Transl. Med. 19:1391
    [Google Scholar]
  111. 111.
    Song J, Wei R, Huo S, Gao J, Liu X. 2022. Metastasis related epithelial-mesenchymal transition signature predicts prognosis and response to immunotherapy in gastric cancer. Front. Immunol. 13:920512
    [Google Scholar]
  112. 112.
    Huang RY-J, Wong MK, Tan TZ, Kuay KT, Ng AHC 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 4:11e915
    [Google Scholar]
  113. 113.
    Gonzalez VD, Samusik N, Chen TJ, Savig ES, Aghaeepour N et al. 2018. Commonly occurring cell subsets in high-grade serous ovarian tumors identified by single-cell mass cytometry. Cell Rep 22:7187588
    [Google Scholar]
  114. 114.
    Grosse-Wilde A, d'Hérouël AF, McIntosh E, Ertaylan G, Skupin A et al. 2015. Stemness of the hybrid epithelial/mesenchymal state in breast cancer and its association with poor survival. PLOS ONE 10:5e0126522
    [Google Scholar]
  115. 115.
    Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K et al. 2017. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 171:7161124.e24
    [Google Scholar]
  116. 116.
    Tagliazucchi GM, Wiecek AJ, Withnell E, Secrier M. 2023. Genomic and microenvironmental heterogeneity shaping epithelial-to-mesenchymal trajectories in cancer. Nat. Commun. 14:789
    [Google Scholar]
  117. 117.
    Janni WJ, Rack B, Terstappen LWMM, Pierga J-Y, Taran F-A et al. 2016. Pooled analysis of the prognostic relevance of circulating tumor cells in primary breast cancer. Clin. Cancer Res. 22:10258393
    [Google Scholar]
  118. 118.
    Kallergi G, Papadaki MA, Politaki E, Mavroudis D, Georgoulias V, Agelaki S. 2011. Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Res 13:3R59
    [Google Scholar]
  119. 119.
    Raimondi C, Gradilone A, Naso G, Vincenzi B, Petracca A et al. 2011. Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res. Treat. 130:244955
    [Google Scholar]
  120. 120.
    Hassan S, Blick T, Thompson EW, Williams ED. 2021. Diversity of epithelial-mesenchymal phenotypes in circulating tumour cells from prostate cancer patient-derived xenograft models. Cancers 13:112750
    [Google Scholar]
  121. 121.
    Cohen EN, Jayachandran G, Gao H, Peabody P, McBride HB et al. 2023. Phenotypic plasticity in circulating tumor cells is associated with poor response to therapy in metastatic breast cancer patients. Cancers 15:51616
    [Google Scholar]
  122. 122.
    Balcik-Ercin P, Cayrefourcq L, Soundararajan R, Mani SA, Alix-Panabières C. 2021. Epithelial-to-mesenchymal plasticity in circulating tumor cell lines sequentially derived from a patient with colorectal cancer. Cancers 13:215408
    [Google Scholar]
  123. 123.
    Shibue T, Weinberg RA. 2017. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 14:1061129
    [Google Scholar]
  124. 124.
    Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM et al. 2009. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. PNAS 106:331382025
    [Google Scholar]
  125. 125.
    Marín-Aguilera M, Codony-Servat J, Reig Ò, Lozano JJ, Fernández PL et al. 2014. Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer. Mol. Cancer Ther. 13:5127084
    [Google Scholar]
  126. 126.
    Bhangu A, Wood G, Brown G, Darzi A, Tekkis P, Goldin R. 2014. The role of epithelial mesenchymal transition and resistance to neoadjuvant therapy in locally advanced rectal cancer. Colorectal Dis 16:4O13343
    [Google Scholar]
  127. 127.
    Lesniak D, Sabri S, Xu Y, Graham K, Bhatnagar P et al. 2013. Spontaneous epithelial-mesenchymal transition and resistance to HER-2-targeted therapies in HER-2-positive luminal breast cancer. PLOS ONE 8:8e71987
    [Google Scholar]
  128. 128.
    Wang L, Saci A, Szabo PM, Chasalow SD, Castillo-Martin M et al. 2018. EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer. Nat. Commun. 9:3503
    [Google Scholar]
  129. 129.
    Kawamoto A, Yokoe T, Tanaka K, Saigusa S, Toiyama Y et al. 2012. Radiation induces epithelial-mesenchymal transition in colorectal cancer cells. Oncol. Rep. 27:15157
    [Google Scholar]
  130. 130.
    Biddle A, Gammon L, Liang X, Costea DE, Mackenzie IC. 2016. Phenotypic plasticity determines cancer stem cell therapeutic resistance in oral squamous cell carcinoma. eBioMedicine 4:13845
    [Google Scholar]
  131. 131.
    Ware KE, Somarelli JA, Schaeffer D, Li J, Zhang T et al. 2016. Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer. OncoTarget 7:315050721
    [Google Scholar]
  132. 132.
    Wu Y, Ginther C, Kim J, Mosher N, Chung S et al. 2012. Expression of Wnt3 activates Wnt/β-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells. Mol. Cancer Res. 10:121597606
    [Google Scholar]
  133. 133.
    Shi R-Z, He Y-F, Wen J, Niu Y-N, Gao Y et al. 2021. Epithelial cell adhesion molecule promotes breast cancer resistance protein-mediated multidrug resistance in breast cancer by inducing partial epithelial-mesenchymal transition. Cell Biol. Int. 45:8164453
    [Google Scholar]
  134. 134.
    Franco DL, Mainez J, Vega S, Sancho P, Murillo MM et al. 2010. Snail1 suppresses TGF-β-induced apoptosis and is sufficient to trigger EMT in hepatocytes. J. Cell Sci. 123:Part 20346777
    [Google Scholar]
  135. 135.
    Escrivà M, Peiró S, Herranz N, Villagrasa P, Dave N et al. 2008. Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation–induced apoptosis. Mol. Cell. Biol. 28:5152840
    [Google Scholar]
  136. 136.
    Wu D-W, Lee M-C, Hsu N-Y, Wu T-C, Wu J-Y et al. 2015. FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction. Oncogene 34:19250515
    [Google Scholar]
  137. 137.
    Lu M, Marsters S, Ye X, Luis E, Gonzalez L, Ashkenazi A. 2014. E-cadherin couples death receptors to the cytoskeleton to regulate apoptosis. Mol. Cell 54:698798
    [Google Scholar]
  138. 138.
    Ayob AZ, Ramasamy TS. 2018. Cancer stem cells as key drivers of tumour progression. J Biomed. Sci. 25:120
    [Google Scholar]
  139. 139.
    Xie S-L, Fan S, Zhang S-Y, Chen W-X, Li Q-X et al. 2018. SOX8 regulates cancer stem-like properties and cisplatin-induced EMT in tongue squamous cell carcinoma by acting on the Wnt/β-catenin pathway. Int. J. Cancer 142:6125265
    [Google Scholar]
  140. 140.
    Li N, Babaei-Jadidi R, Lorenzi F, Spencer-Dene B, Clarke P et al. 2019. An FBXW7-ZEB2 axis links EMT and tumour microenvironment to promote colorectal cancer stem cells and chemoresistance. Oncogenesis 8:313
    [Google Scholar]
  141. 141.
    Liang Y, Hu J, Li J, Liu Y, Yu J et al. 2015. Epigenetic activation of TWIST1 by MTDH promotes cancer stem-like cell traits in breast cancer. Cancer Res 75:17367280
    [Google Scholar]
  142. 142.
    Saxena M, Stephens MA, Pathak H, Rangarajan A. 2011. Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death Dis 2:7e179
    [Google Scholar]
  143. 143.
    Zhang Z, Lee JC, Lin L, Olivas V, Au V et al. 2012. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat. Genet. 44:885260
    [Google Scholar]
  144. 144.
    Byers LA, Diao L, Wang J, Saintigny P, Girard L et al. 2013. An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin. Cancer Res. 19:127990
    [Google Scholar]
  145. 145.
    Gu Y, Zhang Z, ten Dijke P. 2023. Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy. Cell. Mol. Immunol. 20:31840
    [Google Scholar]
  146. 146.
    Lou Y, Diao L, Cuentas ERP, Denning WL, Chen L et al. 2016. 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. 22:14363042
    [Google Scholar]
  147. 147.
    Tseng P-C, Chen C-L, Lee K-Y, Feng P-H, Wang Y-C et al. 2022. Epithelial-to-mesenchymal transition hinders interferon-γ-dependent immunosurveillance in lung cancer cells. Cancer Lett. 539:215712
    [Google Scholar]
  148. 148.
    Akalay I, Janji B, Hasmim M, Noman MZ, André F et al. 2013. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis. Cancer Res. 73:8241827
    [Google Scholar]
  149. 149.
    Dongre A, Rashidian M, Reinhardt F, Bagnato A, Keckesova Z et al. 2017. Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res. 77:15398289
    [Google Scholar]
  150. 150.
    Chen X-H, Liu Z-C, Zhang G, Wei W, Wang X-X et al. 2015. TGF-β and EGF induced HLA-I downregulation is associated with epithelial-mesenchymal transition (EMT) through upregulation of snail in prostate cancer cells. Mol. Immunol. 65:13442
    [Google Scholar]
  151. 151.
    Davis FM, Stewart TA, Thompson EW, Monteith GR. 2014. Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol. Sci. 35:947988
    [Google Scholar]
/content/journals/10.1146/annurev-pathmechdis-051222-122423
Loading
/content/journals/10.1146/annurev-pathmechdis-051222-122423
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error