Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

Key Points

  • The cancer stem cell (CSC) concept posits that a subpopulation of neoplastic cells with stem-cell properties — particularly the capacity to self-renew and give rise to various more differentiated cell types — lies at the apex of a tumour cell hierarchy and serves as a critical driver of tumour progression

  • The phenotypic differences between CSCs and the bulk tumour cells that lack 'stemness' (that is, non-CSCs) seem to be attributable predominantly to epigenetic changes caused by the activation of a epithelial-to-mesenchymal transition (EMT) programme in the former

  • Thus, the CSC paradigm provides an explanation for how epigenetic mechanisms can drive the phenotypic diversity of neoplastic cells — an attribute critical for the development of resistance to therapy

  • Indeed, most conventional therapeutics are inefficient in eradicating carcinoma cells that have entered the CSC state via activation of the EMT programme, thereby permitting CSC-dependent disease relapse

  • Targeting the EMT programme in order to eliminate CSCs offers a promising avenue for the improvement of cancer therapy; however, the success of this approach will require an increase in our mechanistic understanding of the EMT–CSC link

Abstract

The success of anticancer therapy is usually limited by the development of drug resistance. Such acquired resistance is driven, in part, by intratumoural heterogeneity — that is, the phenotypic diversity of cancer cells co-inhabiting a single tumour mass. The introduction of the cancer stem cell (CSC) concept, which posits the presence of minor subpopulations of CSCs that are uniquely capable of seeding new tumours, has provided a framework for understanding one dimension of intratumoural heterogeneity. This concept, taken together with the identification of the epithelial-to-mesenchymal transition (EMT) programme as a critical regulator of the CSC phenotype, offers an opportunity to investigate the nature of intratumoural heterogeneity and a possible mechanistic basis for anticancer drug resistance. In fact, accumulating evidence indicates that conventional therapies often fail to eradicate carcinoma cells that have entered the CSC state via activation of the EMT programme, thereby permitting CSC-mediated clinical relapse. In this Review, we summarize our current understanding of the link between the EMT programme and the CSC state, and also discuss how this knowledge can contribute to improvements in clinical practice.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Morphological and physiological changes associated with the epithelial-to-mesenchymal transition (EMT).
Figure 2: The patterns of epithelial-to-mesenchymal transition (EMT)-programme activation during carcinoma progression.
Figure 3: The contribution of the tumour microenvironment to the activation of the epithelial-to-mesenchymal transition (EMT) programme.
Figure 4: The mechanistic link between the epithelial-to-mesenchymal transition (EMT) programme and cancer stem cell (CSC) status.
Figure 5: The mechanism underlying epithelial-to-mesenchymal transition (EMT)-dependent acquisition of therapeutic resistance.

Similar content being viewed by others

References

  1. Levan, A. & Hauschka, T. S. Endomitotic reduplication mechanisms in ascites tumors of the mouse. J. Natl Cancer Inst. 14, 1–43 (1953).

    CAS  PubMed  Google Scholar 

  2. Makino, S. Further evidence favoring the concept of the stem cell in ascites tumors of rats. Ann. NY Acad. Sci. 63, 818–830 (1956).

    CAS  PubMed  Google Scholar 

  3. Prehn, R. T. Analysis of antigenic heterogeneity within individual 3-methylcholanthrene-induced mouse sarcomas. J. Natl Cancer Inst. 45, 1039–1045 (1970).

    CAS  PubMed  Google Scholar 

  4. Mitelman, F. The chromosomes of fifty primary Rous rat sarcomas. Hereditas 69, 155–186 (1971).

    CAS  PubMed  Google Scholar 

  5. Alizadeh, A. A. et al. Toward understanding and exploiting tumor heterogeneity. Nat. Med. 21, 846–853 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Easwaran, H., Tsai, H. C. & Baylin, S. B. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol. Cell 54, 716–727 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Burrell, R. A., McGranahan, N., Bartek, J. & Swanton, C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501, 338–345 (2013).

    CAS  PubMed  Google Scholar 

  8. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Garraway, L. A. & Lander, E. S. Lessons from the cancer genome. Cell 153, 17–37 (2013).

    CAS  PubMed  Google Scholar 

  10. Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 358, 1148–1159 (2008).

    CAS  PubMed  Google Scholar 

  11. Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).

    CAS  PubMed  Google Scholar 

  12. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    CAS  PubMed  Google Scholar 

  13. Bjerkvig, R., Tysnes, B. B., Aboody, K. S., Najbauer, J. & Terzis, A. J. The origin of the cancer stem cell: current controversies and new insights. Nat. Rev. Cancer 5, 899–904 (2005).

    CAS  PubMed  Google Scholar 

  14. Avgustinova, A. & Benitah, S. A. Epigenetic control of adult stem cell function. Nat. Rev. Mol. Cell Biol. 17, 643–658 (2016).

    CAS  PubMed  Google Scholar 

  15. Brabletz, T., Jung, A., Spaderna, S., Hlubek, F. & Kirchner, T. Migrating cancer stem cells — an integrated concept of malignant tumour progression. Nat. Rev. Cancer 5, 744–749 (2005).

    CAS  PubMed  Google Scholar 

  16. Wicha, M. S., Liu, S. & Dontu, G. Cancer stem cells: an old idea — a paradigm shift. Cancer Res. 66, 1883–1890 (2006).

    CAS  PubMed  Google Scholar 

  17. Kreso, A. & Dick, J. E. Evolution of the cancer stem cell model. Cell Stem Cell 14, 275–291 (2014).

    CAS  PubMed  Google Scholar 

  18. Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5, 275–284 (2005).

    CAS  PubMed  Google Scholar 

  19. Clarke, M. F. et al. Cancer stem cells — perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66, 9339–9344 (2006).

    CAS  PubMed  Google Scholar 

  20. Eyler, C. E. & Rich, J. N. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J. Clin. Oncol. 26, 2839–2845 (2008).

    CAS  PubMed  Google Scholar 

  21. Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).

    CAS  PubMed  Google Scholar 

  22. Li, X. et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl Cancer Inst. 100, 672–679 (2008).

    CAS  PubMed  Google Scholar 

  23. Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Polyak, K. & Weinberg, R. A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 9, 265–273 (2009).

    CAS  PubMed  Google Scholar 

  25. Medema, J. P. Cancer stem cells: the challenges ahead. Nat. Cell Biol. 15, 338–344 (2013).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen, Y. C. et al. Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem. Biophys. Res. Commun. 385, 307–313 (2009).

    CAS  PubMed  Google Scholar 

  29. Pang, R. et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 6, 603–615 (2010).

    CAS  PubMed  Google Scholar 

  30. Mulholland, D. J. et al. Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res. 72, 1878–1889 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Morel, A. P. et al. Generation of breast cancer stem cells through epithelial–mesenchymal transition. PLoS ONE 3, e2888 (2008).

    PubMed  PubMed Central  Google Scholar 

  32. Wellner, U. et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat. Cell Biol. 11, 1487–1495 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Holohan, C., Van Schaeybroeck, S., Longley, D. B. & Johnston, P. G. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13, 714–726 (2013).

    CAS  PubMed  Google Scholar 

  35. Shook, D. & Keller, R. Mechanisms, mechanics and function of epithelial–mesenchymal transitions in early development. Mech. Dev. 120, 1351–1383 (2003).

    CAS  PubMed  Google Scholar 

  36. Hay, E. D. The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev. Dyn. 233, 706–720 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  40. Taube, J. H. et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc. Natl Acad. Sci. USA 107, 15449–15454 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  46. Hugo, H. J. et al. Defining the E-cadherin repressor interactome in epithelial–mesenchymal transition: the PMC42 model as a case study. Cells Tissues Organs 193, 23–40 (2011).

    PubMed  Google Scholar 

  47. Diaz-Lopez, A., Moreno-Bueno, G. & Cano, A. Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives. Cancer Manag. Res. 6, 205–216 (2014).

    PubMed  PubMed Central  Google Scholar 

  48. Burk, U. et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 9, 582–589 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  50. Kim, N. H. et al. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial–mesenchymal transition. J. Cell Biol. 195, 417–433 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Chen, A. et al. The ubiquitin ligase Siah is a novel regulator of Zeb1 in breast cancer. Oncotarget 6, 862–873 (2015).

    CAS  PubMed  Google Scholar 

  55. Thiery, J. P. Epithelial–mesenchymal transitions in development and pathologies. Curr. Opin. Cell Biol. 15, 740–746 (2003).

    CAS  PubMed  Google Scholar 

  56. Carver, E. A., Jiang, R., Lan, Y., Oram, K. F. & Gridley, T. The mouse snail gene encodes a key regulator of the epithelial–mesenchymal transition. Mol. Cell. Biol. 21, 8184–8188 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Chen, Z. F. & Behringer, R. R. Twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 9, 686–699 (1995).

    CAS  PubMed  Google Scholar 

  58. Van de Putte, T. et al. Mice lacking ZFHX1B, the gene that codes for Smad-interacting protein-1, reveal a role for multiple neural crest cell defects in the etiology of Hirschsprung disease–mental retardation syndrome. Am. J. Hum. Genet. 72, 465–470 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Jiang, R., Lan, Y., Norton, C. R., Sundberg, J. P. & Gridley, T. The Slug gene is not essential for mesoderm or neural crest development in mice. Dev. Biol. 198, 277–285 (1998).

    CAS  PubMed  Google Scholar 

  60. Higashi, Y. et al. Impairment of T cell development in δ EF1 mutant mice. J. Exp. Med. 185, 1467–1479 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Sosic, D., Richardson, J. A., Yu, K., Ornitz, D. M. & Olson, E. N. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-κB activity. Cell 112, 169–180 (2003).

    CAS  PubMed  Google Scholar 

  62. Bain, G. et al. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell 79, 885–892 (1994).

    CAS  PubMed  Google Scholar 

  63. Zhuang, Y., Soriano, P. & Weintraub, H. The helix-loop-helix gene E2A is required for B cell formation. Cell 79, 875–884 (1994).

    CAS  PubMed  Google Scholar 

  64. Yao, D., Dai, C. & Peng, S. Mechanism of the mesenchymal–epithelial transition and its relationship with metastatic tumor formation. Mol. Cancer Res. 9, 1608–1620 (2011).

    CAS  PubMed  Google Scholar 

  65. Gunasinghe, N. P., Wells, A., Thompson, E. W. & Hugo, H. J. Mesenchymal–epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Metastasis Rev. 31, 469–478 (2012).

    CAS  PubMed  Google Scholar 

  66. Li, R. et al. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 7, 51–63 (2010).

    CAS  PubMed  Google Scholar 

  67. Little, M. H. & McMahon, A. P. Mammalian kidney development: principles, progress, and projections. Cold Spring Harb. Perspect. Biol. 4, a008300 (2012).

    PubMed  PubMed Central  Google Scholar 

  68. Ledford, H. Cancer theory faces doubts. Nature 472, 273 (2011).

    CAS  PubMed  Google Scholar 

  69. Tarin, D., Thompson, E. W. & Newgreen, D. F. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res. 65, 5996–6000 (2005).

    CAS  PubMed  Google Scholar 

  70. Thompson, L., Chang, B. & Barsky, S. H. Monoclonal origins of malignant mixed tumors (carcinosarcomas). Evidence for a divergent histogenesis. Am. J. Surg. Pathol. 20, 277–285 (1996).

    CAS  PubMed  Google Scholar 

  71. Mareel, M., Vleminckx, K., Vermeulen, S., Bracke, M. & Van Roy, F. E-Cadherin expression: a counterbalance for cancer cell invasion. Bull. Cancer 79, 347–355 (1992).

    CAS  PubMed  Google Scholar 

  72. Birchmeier, W. & Behrens, J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim. Biophys. Acta 1198, 11–26 (1994).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  77. Soltermann, A. et al. Prognostic significance of epithelial-mesenchymal and mesenchymal–epithelial transition protein expression in non-small cell lung cancer. Clin. Cancer Res. 14, 7430–7437 (2008).

    CAS  PubMed  Google Scholar 

  78. Rasheed, Z. A. et al. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J. Natl Cancer Inst. 102, 340–351 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  80. Spaderna, S. et al. A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastroenterology 131, 830–840 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  82. Yu, M. et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580–584 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Weinstein, R. S., Merk, F. B. & Alroy, J. The structure and function of intercellular junctions in cancer. Adv. Cancer Res. 23, 23–89 (1976).

    CAS  PubMed  Google Scholar 

  84. Gabbert, H., Wagner, R., Moll, R. & Gerharz, C. D. Tumor dedifferentiation: an important step in tumor invasion. Clin. Exp. Metastasis 3, 257–279 (1985).

    CAS  PubMed  Google Scholar 

  85. Cheung, K. J., Gabrielson, E., Werb, Z. & Ewald, A. J. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155, 1639–1651 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Mayer, B. et al. E-Cadherin expression in primary and metastatic gastric cancer: down-regulation correlates with cellular dedifferentiation and glandular disintegration. Cancer Res. 53, 1690–1695 (1993).

    CAS  PubMed  Google Scholar 

  87. Brabletz, T. et al. Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc. Natl Acad. Sci. USA 98, 10356–11036 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Lawson, D. A. et al. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature 526, 131–135 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Berx, G. et al. E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 13, 1919–1925 (1996).

    CAS  PubMed  Google Scholar 

  92. Husemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58–68 (2008).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Pantel, K., Alix-Panabieres, C. & Riethdorf, S. Cancer micrometastases. Nat. Rev. Clin. Oncol. 6, 339–351 (2009).

    CAS  PubMed  Google Scholar 

  96. Klein, C. A. Selection and adaptation during metastatic cancer progression. Nature 501, 365–372 (2013).

    CAS  PubMed  Google Scholar 

  97. Trimboli, A. J. et al. Direct evidence for epithelial–mesenchymal transitions in breast cancer. Cancer Res. 68, 937–945 (2008).

    CAS  PubMed  Google Scholar 

  98. Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).

    CAS  PubMed  Google Scholar 

  99. Mueller, M. M. & Fusenig, N. E. Friends or foes — bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4, 839–849 (2004).

    CAS  PubMed  Google Scholar 

  100. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).

    CAS  PubMed  Google Scholar 

  101. Ohlund, D., Elyada, E. & Tuveson, D. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211, 1503–1523 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  103. Hayward, S. W. et al. Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Res. 61, 8135–8142 (2001).

    CAS  PubMed  Google Scholar 

  104. Giannoni, E. et al. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial–mesenchymal transition and cancer stemness. Cancer Res. 70, 6945–6956 (2010).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  106. Nielsen, B. S., Sehested, M., Timshel, S., Pyke, C. & Dano, K. Messenger RNA for urokinase plasminogen activator is expressed in myofibroblasts adjacent to cancer cells in human breast cancer. Lab. Invest. 74, 168–177 (1996).

    CAS  PubMed  Google Scholar 

  107. Martin, M., Pujuguet, P. & Martin, F. Role of stromal myofibroblasts infiltrating colon cancer in tumor invasion. Pathol. Res. Pract. 192, 712–717 (1996).

    CAS  PubMed  Google Scholar 

  108. Nakayama, H. et al. The role of myofibroblasts at the tumor border of invasive colorectal adenocarcinomas. Jpn J. Clin. Oncol. 28, 615–620 (1998).

    CAS  PubMed  Google Scholar 

  109. Sparmann, A. & Bar-Sagi, D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6, 447–458 (2004).

    CAS  PubMed  Google Scholar 

  110. Yang, G. et al. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc. Natl Acad. Sci. USA 103, 16472–164773 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Kim, H., Choi, J. A. & Kim, J. H. Ras promotes transforming growth factor-β (TGF-β)-induced epithelial–mesenchymal transition via a leukotriene B4 receptor-2-linked cascade in mammary epithelial cells. J. Biol. Chem. 289, 22151–22160 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Li, Y., Wang, L., Pappan, L., Galliher-Beckley, A. & Shi, J. IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation. Mol. Cancer 11, 87 (2012).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  119. Kumar, V., Patel, S., Tcyganov, E. & Gabrilovich, D. I. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37, 208–220 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Powell, D. R. & Huttenlocher, A. Neutrophils in the tumor microenvironment. Trends Immunol. 37, 41–52 (2016).

    CAS  PubMed  Google Scholar 

  121. Freisinger, C. M. & Huttenlocher, A. Live imaging and gene expression analysis in zebrafish identifies a link between neutrophils and epithelial to mesenchymal transition. PLoS ONE 9, e112183 (2014).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Krishnamachary, B. et al. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel–Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res. 66, 2725–2731 (2006).

    CAS  PubMed  Google Scholar 

  124. Esteban, M. A. et al. Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res. 66, 3567–3575 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Lester, R. D., Jo, M., Montel, V., Takimoto, S. & Gonias, S. L. uPAR induces epithelial–mesenchymal transition in hypoxic breast cancer cells. J. Cell Biol. 178, 425–436 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  128. Thompson, E. W., Newgreen, D. F. & Tarin, D. Carcinoma invasion and metastasis: a role for epithelial–mesenchymal transition? Cancer Res. 65, 5991–5995 (2005).

    CAS  PubMed  Google Scholar 

  129. Fidler, I. J. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat. Rev. Cancer 3, 453–458 (2003).

    CAS  PubMed  Google Scholar 

  130. Scheel, C. & Weinberg, R. A. Cancer stem cells and epithelial–mesenchymal transition: concepts and molecular links. Semin. Cancer Biol. 22, 396–403 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Gupta, P. B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011).

    CAS  PubMed  Google Scholar 

  133. Chaffer, C. L. et al. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154, 61–74 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Baccelli, I. & Trumpp, A. The evolving concept of cancer and metastasis stem cells. J. Cell Biol. 198, 281–293 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Waerner, T. et al. ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell 10, 227–239 (2006).

    CAS  PubMed  Google Scholar 

  136. Onder, T. T. et al. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 68, 3645–3654 (2008).

    CAS  PubMed  Google Scholar 

  137. Del Pozo Martin, Y. et al. Mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization. Cell Rep. 13, 2456–2469 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Barkan, D. et al. Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Res. 68, 6241–6250 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Shibue, T. & Weinberg, R. A. Integrin β1-focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs. Proc. Natl Acad. Sci. USA 106, 10290–10295 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Shibue, T., Brooks, M. W. Inan, M. F., Reinhardt, F. & Weinberg, R. A. The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discov. 2, 706–721 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Shibue, T., Brooks, M. W. & Weinberg, R. A. An integrin-linked machinery of cytoskeletal regulation that enables experimental tumor initiation and metastatic colonization. Cancer Cell 24, 481–498 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Ni, T. et al. Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer. Nat. Cell Biol. 18, 1221–1232 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Kim, J. et al. Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity. Proc. Natl Acad. Sci. USA 109, 6124–6129 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Liu, S. et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2, 78–91 (2014).

    CAS  Google Scholar 

  148. Jolly, M. K. et al. Coupling the modules of EMT and stemness: a tunable 'stemness window' model. Oncotarget 6, 25161–25174 (2015).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Al-Hajj, M., Becker, M. W., Wicha, M., Weissman, I. & Clarke, M. F. Therapeutic implications of cancer stem cells. Curr. Opin. Genet. Dev. 14, 43–47 (2004).

    CAS  PubMed  Google Scholar 

  151. Lerner, C. & Harrison, D. E. 5-Fluorouracil spares hemopoietic stem cells responsible for long-term repopulation. Exp. Hematol. 18, 114–118 (1990).

    CAS  PubMed  Google Scholar 

  152. Bouwens, L. & De Blay, E. Islet morphogenesis and stem cell markers in rat pancreas. J. Histochem. Cytochem. 44, 947–951 (1996).

    CAS  PubMed  Google Scholar 

  153. Peters, R., Leyvraz, S. & Perey, L. Apoptotic regulation in primitive hematopoietic precursors. Blood 92, 2041–2052 (1998).

    CAS  PubMed  Google Scholar 

  154. Feuerhake, F., Sigg, W., Hofter, E. A., Dimpfl, T. & Welsch, U. Immunohistochemical analysis of Bcl-2 andBax expression in relation to cell turnover and epithelial differentiation markers in the non-lactating human mammary gland epithelium. Cell Tissue Res. 299, 47–58 (2000).

    CAS  PubMed  Google Scholar 

  155. Zhou, S. et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat. Med. 7, 1028–1034 (2001).

    CAS  PubMed  Google Scholar 

  156. Potten, C. S. & Loeffler, M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110, 1001–1020 (1990).

    CAS  PubMed  Google Scholar 

  157. Levina, V., Marrangoni, A. M., DeMarco, R., Gorelik, E. & Lokshin, A. E. Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. PLoS ONE 3, e3077 (2008).

    PubMed  PubMed Central  Google Scholar 

  158. Dallas, N. A. et al. Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 69, 1951–1957 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Graham, S. M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99, 319–325 (2002).

    CAS  PubMed  Google Scholar 

  160. Kottke, T. et al. Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors. Nat. Med. 17, 854–859 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Boisgerault, N. et al. Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse. Mol. Ther. 21, 1507–1516 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Farmer, P. et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat. Med. 15, 68–74 (2009).

    CAS  PubMed  Google Scholar 

  163. Byers, L. A. et al. An epithelial–mesenchymal transition 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, 279–290 (2013).

    CAS  PubMed  Google Scholar 

  164. Bierie, B. & Moses, H. L. Tumour microenvironment: TGFβ: the molecular Jekyll and Hyde of cancer. Nat. Rev. Cancer 6, 506–520 (2006).

    CAS  PubMed  Google Scholar 

  165. Massague, J. TGFβ signalling in context. Nat. Rev. Mol. Cell Biol. 13, 616–630 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Deheuninck, J. & Luo, K. Ski and SnoN, potent negative regulators of TGF-β signaling. Cell Res. 19, 47–57 (2009).

    CAS  PubMed  Google Scholar 

  167. Akhurst, R. J. & Hata, A. Targeting the TGFβ signalling pathway in disease. Nat. Rev. Drug Discov. 11, 790–811 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Neuzillet, C. et al. Targeting the TGFβ pathway for cancer therapy. Pharmacol. Ther. 147, 22–31 (2015).

    CAS  PubMed  Google Scholar 

  169. Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G. F. Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol. 4, 915–925 (2003).

    CAS  PubMed  Google Scholar 

  170. Gherardi, E., Birchmeier, W., Birchmeier, C. & Vande Woude, G. Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer 12, 89–103 (2012).

    CAS  PubMed  Google Scholar 

  171. Scagliotti, G. V., Novello, S. & von Pawel, J. The emerging role of MET/HGF inhibitors in oncology. Cancer Treat. Rev. 39, 793–801 (2013).

    CAS  PubMed  Google Scholar 

  172. Joyce, J. A. Therapeutic targeting of the tumor microenvironment. Cancer Cell 7, 513–520 (2005).

    CAS  PubMed  Google Scholar 

  173. Albini, A. & Sporn, M. B. The tumour microenvironment as a target for chemoprevention. Nat. Rev. Cancer 7, 139–147 (2007).

    CAS  PubMed  Google Scholar 

  174. Bargagna-Mohan, P. et al. The tumor inhibitor and antiangiogenic agent withaferin A targets the intermediate filament protein vimentin. Chem. Biol. 14, 623–634 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Thaiparambil, J. T. et al. Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation. Int. J. Cancer 129, 2744–2755 (2011).

    CAS  PubMed  Google Scholar 

  176. Tanaka, H. et al. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat. Med. 16, 1414–1420 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Hafizi, S. & Dahlback, B. Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine Growth Factor Rev. 17, 295–304 (2006).

    CAS  PubMed  Google Scholar 

  178. Gjerdrum, C. et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc. Natl Acad. Sci. USA 107, 1124–1129 (2010).

    CAS  PubMed  Google Scholar 

  179. Sheridan, C. First Axl inhibitor enters clinical trials. Nat. Biotechnol. 31, 775–776 (2013).

    CAS  PubMed  Google Scholar 

  180. Byers, L. et al. A phase I/II and pharmacokinetic study of BGB324, a selective AXL inhibitor as monotherapy and in combination with erlotinib in patients with advanced non-small cell lung cancer (NSCLC). Eur. J. Cancer 69, S18–S19 (2017).

    Google Scholar 

  181. Gupta, P. B. et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138, 645–659 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Tallman, M. S. & Altman, J. K. How I treat acute promyelocytic leukemia. Blood 114, 5126–5135 (2009).

    CAS  PubMed  Google Scholar 

  184. Pattabiraman, D. R. et al. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. Science 351, aad3680 (2016).

    PubMed  PubMed Central  Google Scholar 

  185. Clevers, H. The cancer stem cell: premises, promises and challenges. Nat. Med. 17, 313–319 (2011).

    CAS  PubMed  Google Scholar 

  186. Marcucci, F., Stassi, G. & De Maria, R. Epithelial–mesenchymal transition: a new target in anticancer drug discovery. Nat. Rev. Drug Discov. 15, 311–325 (2016).

    CAS  PubMed  Google Scholar 

  187. Schmidt, J. M. et al. Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. Cell Rep. 10, 131–139 (2015).

    CAS  PubMed  Google Scholar 

  188. Marjanovic, N. D., Weinberg, R. A. & Chaffer, C. L. Cell plasticity and heterogeneity in cancer. Clin. Chem. 59, 168–179 (2013).

    CAS  PubMed  Google Scholar 

  189. Clark, A. G. & Vignjevic, D. M. Modes of cancer cell invasion and the role of the microenvironment. Curr. Opin. Cell Biol. 36, 13–22 (2015).

    CAS  PubMed  Google Scholar 

  190. Hennessy, B. T. et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 69, 4116–4124 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Shimono, Y. et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138, 592–603 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Leung, E. L. H. et al. Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS ONE 5, e14062 (2010).

    PubMed  PubMed Central  Google Scholar 

  193. Pirozzi, G. et al. Epithelial to mesenchymal transition by TGFβ-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PLoS ONE 6, e21548 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Kong, D. J. et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS ONE 5, e12445 (2010).

    PubMed  PubMed Central  Google Scholar 

  195. Wu, W. S. et al. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 123, 641–653 (2005).

    CAS  PubMed  Google Scholar 

  196. Wu, D. W. et al. FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction. Oncogene 34, 3882–3883 (2015).

    CAS  PubMed  Google Scholar 

  197. Vega, S. et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 18, 1131–1143 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Escriva, M. et al. Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Mol. Cell. Biol. 28, 1528–1540 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Lu, M. et al. E-cadherin couples death receptors to the cytoskeleton to regulate apoptosis. Mol. Cell 54, 987–998 (2014).

    CAS  PubMed  Google Scholar 

  200. Saxena, M., Stephens, M. A., Pathak, H. & Rangarajan, A. Transcription factors that mediate epithelial–mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death Dis. 2, e179 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl Med. 3, 75ra26 (2011).

    PubMed  PubMed Central  Google Scholar 

  202. Zhang, Z. et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat. Genet. 44, 852–860 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Kudo-Saito, C., Shirako, H., Takeuchi, T. & Kawakami, Y. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 15, 195–206 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Arthur W. Lambert (Whitehead Institute for Biomedical Research) for critically reading the draft of this article and providing invaluable comments. T.S. has received postdoctoral fellowships from the Human Frontier Science Program, the Japan Society for the Promotion of Science, and the Ludwig Fund for Cancer Research. R.A.W. is an American Cancer Society research professor and a Daniel K. Ludwig Foundation cancer research professor. The work of the authors has been funded by grants from the National Institutes of Health (P01 CA080111), the Breast Cancer Research Foundation, the Waxman Foundation, and the Virginia & Daniel K. Ludwig Fund for Cancer Research.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert A. Weinberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shibue, T., Weinberg, R. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14, 611–629 (2017). https://doi.org/10.1038/nrclinonc.2017.44

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2017.44

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer