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The epithelial–mesenchymal plasticity landscape: principles of design and mechanisms of regulation

Abstract

Epithelial–mesenchymal plasticity (EMP) enables cells to interconvert between several states across the epithelial–mesenchymal landscape, thereby acquiring hybrid epithelial/mesenchymal phenotypic features. This plasticity is crucial for embryonic development and wound healing, but also underlies the acquisition of several malignant traits during cancer progression. Recent research using systems biology and single-cell profiling methods has provided novel insights into the main forces that shape EMP, which include the microenvironment, lineage specification and cell identity, and the genome. Additionally, key roles have emerged for hysteresis (cell memory) and cellular noise, which can drive stochastic transitions between cell states. Here, we review these forces and the distinct but interwoven layers of regulatory control that stabilize EMP states or facilitate epithelial–mesenchymal transitions (EMTs) and discuss the therapeutic potential of manipulating the EMP landscape.

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Fig. 1: Epithelial cells inhabit a landscape of plasticity.
Fig. 2: The developmental landscape guides EMP.
Fig. 3: EMT is controlled by hysteretic control mechanisms.
Fig. 4: Noise-driven stochastic state transitions enable spontaneous emergence of phenotypic heterogeneity.
Fig. 5: Several levels of regulation control EMT.
Fig. 6: Phenotypic stability factors interact with the core regulatory EMT network to stabilize the hybrid EMT state.

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References

  1. Waddington, C. H. The Strategy of the Genes (Routledge, 2014).

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Yang, J. et al. Guidelines and definitions for research on epithelial–mesenchymal transition. Nat. Rev. Mol. Cell Biol. 21, 341–352 (2020). This consensus statement clarifies the nomenclature used in the EMT field and provides guidelines for EMT research.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hay, E. D. in Epithelial–Mesenchymal Interactions; 18th Hahnemann Symposium (eds Fleischmajer, R. & Billingham, R. E.) 31–35 (Williams & Wilkins, 1968).

  6. Hay, E. D. An overview of epithelio-mesenchymal transformation. Acta Anat. 154, 8–20 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Thiery, J. P. Epithelial–mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Cook, D. P. & Vanderhyden, B. C. Context specificity of the EMT transcriptional response. Nat. Commun. 11, 2142 (2020). This comparative analysis uses time-course, single-cell RNA sequencing of EMT responses that highlights their diversity across systems.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dong, J. et al. Single-cell RNA-seq analysis unveils a prevalent epithelial/mesenchymal hybrid state during mouse organogenesis. Genome Biol. 19, 31 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhao, J. et al. Single cell RNA-seq reveals the landscape of tumor and infiltrating immune cells in nasopharyngeal carcinoma. Cancer Lett. 477, 131–143 (2020).

    Article  CAS  PubMed  Google Scholar 

  12. Ji, A. L. et al. Multimodal analysis of composition and spatial architecture in human squamous cell carcinoma. Cell 182, 1661–1662 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McFaline-Figueroa, J. L. et al. A pooled single-cell genetic screen identifies regulatory checkpoints in the continuum of the epithelial-to-mesenchymal transition. Nat. Genet. 51, 1389–1398 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Deshmukh, A. P. et al. Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2102050118 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Simeonov, K. P. et al. Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states. Cancer Cell 39, 1150–1162.e9 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pastushenko, I. et al. Identification of the tumour transition states occurring during EMT. Nature 556, 463–468 (2018). Using a large panel of cell surface markers, this study is the first to provide strong, in vivo evidence for intermediate EMT states with distinct functional characteristics.

    Article  CAS  PubMed  Google Scholar 

  17. Karacosta, L. G. et al. Mapping lung cancer epithelial–mesenchymal transition states and trajectories with single-cell resolution. Nat. Commun. 10, 5587 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Taverna, J. A. et al. Single-cell proteomic profiling identifies combined AXL and JAK1 inhibition as a novel therapeutic strategy for lung cancer. Cancer Res. 80, 1551–1563 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pastushenko, I. & Blanpain, C. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 29, 212–226 (2019).

    Article  CAS  PubMed  Google Scholar 

  20. Pastushenko, I. et al. Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis. Nature 589, 448–455 (2021).

    Article  CAS  PubMed  Google Scholar 

  21. Kroger, C. et al. Acquisition of a hybrid E/M state is essential for tumorigenicity of basal breast cancer cells. Proc. Natl Acad. Sci. USA 116, 7353–7362 (2019). This study finds that a hybrid EMT state results in high tumorigenic potential, whereas fully epithelial or mesenchymal cells, or a combination thereof, show poor tumorigenic potential.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Potts, J. D. & Runyan, R. B. Epithelial–mesenchymal cell transformation in the embryonic heart can be mediated, in part, by transforming growth factor β. Dev. Biol. 134, 392–401 (1989).

    Article  CAS  PubMed  Google Scholar 

  23. Miettinen, P. J., Ebner, R., Lopez, A. R. & Derynck, R. TGF-β induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J. Cell Biol. 127, 2021–2036 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Stoker, M. & Perryman, M. An epithelial scatter factor released by embryo fibroblasts. J. Cell Sci. 77, 209–223 (1985).

    Article  CAS  PubMed  Google Scholar 

  25. Valles, A. M. et al. Acidic fibroblast growth factor is a modulator of epithelial plasticity in a rat bladder carcinoma cell line. Proc. Natl Acad. Sci. USA 87, 1124–1128 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim, K., Lu, Z. & Hay, E. D. Direct evidence for a role of β-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol. Int. 26, 463–476 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Loayza-Puch, F. et al. TGFβ1-induced leucine limitation uncovered by differential ribosome codon reading. EMBO Rep. 18, 549–557 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Recouvreux, M. V. et al. Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer. J. Exp. Med. https://doi.org/10.1084/jem.20200388 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Nakasuka, F. et al. TGF-β-dependent reprogramming of amino acid metabolism induces epithelial–mesenchymal transition in non-small cell lung cancers. Commun. Biol. 4, 782 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Heise, R. L., Stober, V., Cheluvaraju, C., Hollingsworth, J. W. & Garantziotis, S. Mechanical stretch induces epithelial–mesenchymal transition in alveolar epithelia via hyaluronan activation of innate immunity. J. Biol. Chem. 286, 17435–17444 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Przybyla, L., Muncie, J. M. & Weaver, V. M. Mechanical control of epithelial-to-mesenchymal transitions in development and cancer. Annu. Rev. Cell Dev. Biol. 32, 527–554 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Zhao, X., Hu, J., Li, Y. & Guo, M. Volumetric compression develops noise-driven single-cell heterogeneity. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2110550118 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Fattet, L. et al. Matrix rigidity controls epithelial–mesenchymal plasticity and tumor metastasis via a mechanoresponsive EPHA2/LYN complex. Dev. Cell 54, 302–316.e7 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Deng, Y., Chakraborty, P., Jolly, M. K. & Levine, H. A theoretical approach to coupling the epithelial–mesenchymal transition (EMT) to extracellular matrix (ECM) stiffness via LOXL2. Cancers https://doi.org/10.3390/cancers13071609 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Gao, Y. et al. Metastasis organotropism: redefining the congenial soil. Dev. Cell 49, 375–391 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Labelle, M., Begum, S. & Hynes, R. O. Direct signaling between platelets and cancer cells induces an epithelial–mesenchymal-like transition and promotes metastasis. Cancer Cell 20, 576–590 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kan, T. et al. Single-cell EMT-related transcriptional analysis revealed intra-cluster heterogeneity of tumor cell clusters in epithelial ovarian cancer ascites. Oncogene 39, 4227–4240 (2020).

    Article  CAS  PubMed  Google Scholar 

  41. Szczerba, B. M. et al. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature 566, 553 (2019).

    Article  CAS  PubMed  Google Scholar 

  42. Liu, Q., Liao, Q. & Zhao, Y. Myeloid-derived suppressor cells (MDSC) facilitate distant metastasis of malignancies by shielding circulating tumor cells (CTC) from immune surveillance. Med. Hypotheses 87, 34–39 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Sprouse, M. L. et al. PMN-MDSCs enhance CTC metastatic properties through reciprocal interactions via ROS/Notch/nodal signaling. Int. J. Mol. Sci. https://doi.org/10.3390/ijms20081916 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hurtado, P., Martinez-Pena, I. & Pineiro, R. Dangerous liaisons: circulating tumor cells (CTCs) and cancer-associated fibroblasts (CAFs). Cancers https://doi.org/10.3390/cancers12102861 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Xiong, G. et al. Hsp47 promotes cancer metastasis by enhancing collagen-dependent cancer cell–platelet interaction. Proc. Natl Acad. Sci. USA 117, 3748–3758 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hou, J. M. et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J. Clin. Oncol. 30, 525–532 (2012).

    Article  PubMed  Google Scholar 

  47. Paoli, P., Giannoni, E. & Chiarugi, P. Anoikis molecular pathways and its role in cancer progression. Biochim. Biophys. Acta 1833, 3481–3498 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Giuliano, M. et al. Perspective on circulating tumor cell clusters: why it takes a village to metastasize. Cancer Res. 78, 845–852 (2018).

    Article  CAS  PubMed  Google Scholar 

  49. Aceto, N. et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110–1122 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cheung, K. J. et al. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc. Natl Acad. Sci. USA 113, E854–E863 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sarioglu, A. F. et al. A microfluidic device for label-free, physical capture of circulating tumor cell clusters. Nat. Methods 12, 685–691 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Beard, J. Embryological aspects and etiology of carcinoma. Lancet 159, 1758–1761 (1902).

    Article  Google Scholar 

  53. Virchow, R. Vorlesungen über cellularpathologie in ihrer Begründung auf physiologischer und pathologischer Gewebelehre (Verlag August Hirschwald, 1858).

  54. Markert, C. L. Neoplasia: a disease of cell differentiation. Cancer Res. 28, 1908–1914 (1968).

    CAS  PubMed  Google Scholar 

  55. Micalizzi, D. S., Farabaugh, S. M. & Ford, H. L. Epithelial–mesenchymal transition in cancer: parallels between normal development and tumor progression. J. Mammary Gland. Biol. 15, 117–134 (2010).

    Article  Google Scholar 

  56. Nieto, M. A. Epithelial plasticity: a common theme in embryonic and cancer cells. Science 342, 1234850 (2013).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  58. Pritchard, C. et al. Conserved gene expression programs integrate mammalian prostate development and tumorigenesis. Cancer Res. 69, 1739–1747 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Pomerantz, M. M. et al. Prostate cancer reactivates developmental epigenomic programs during metastatic progression. Nat. Genet. 52, 790–799 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Schaeffer, E. M. et al. Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer. Oncogene 27, 7180–7191 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Roe, J. S. et al. Enhancer reprogramming promotes pancreatic cancer metastasis. Cell 170, 875–888.e20 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gupta, P. B. et al. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nat. Genet. 37, 1047–1054 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Holczbauer, A. et al. Modeling pathogenesis of primary liver cancer in lineage-specific mouse cell types. Gastroenterology 145, 221–231 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Latil, M. et al. Cell-type-specific chromatin states differentially prime squamous cell carcinoma tumor-initiating cells for epithelial to mesenchymal transition. Cell Stem Cell 20, 191–204.e5 (2017). This study illustrates how the cancer cell of origin controls EMT propensity during further tumour development through transcriptional and epigenetic priming.

    Article  CAS  PubMed  Google Scholar 

  65. Chou, J., Provot, S. & Werb, Z. GATA3 in development and cancer differentiation: cells GATA have it! J. Cell. Physiol. 222, 42–49 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bai, F. et al. GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer. Theranostics 11, 8218 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Saotome, M., Poduval, D. B., Nair, R., Cooper, M. & Takaku, M. GATA3 truncation mutants alter EMT related gene expression via partial motif recognition in luminal breast cancer cells. Front. Genet. 13, 67 (2022).

    Article  Google Scholar 

  68. Kouros-Mehr, H. et al. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell 13, 141–152 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yan, W., Cao, Q. J., Arenas, R. B., Bentley, B. & Shao, R. GATA3 inhibits breast cancer metastasis through the reversal of epithelial–mesenchymal transition. J. Biol. Chem. 285, 14042–14051 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Li, Y. et al. Loss of GATA3 in bladder cancer promotes cell migration and invasion. Cancer Biol. Ther. 15, 428–435 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Chakrabarti, R. et al. Elf5 inhibits the epithelial–mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2. Nat. Cell Biol. 14, 1212–1222 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wu, B. et al. Epigenetic regulation of Elf5 is associated with epithelial–mesenchymal transition in urothelial cancer. PLoS ONE 10, e0117510 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Yao, B. et al. Elf5 inhibits TGF‐β‐driven epithelial–mesenchymal transition in prostate cancer by repressing SMAD3 activation. Prostate 75, 872–882 (2015).

    Article  CAS  PubMed  Google Scholar 

  74. Song, Y., Washington, M. K. & Crawford, H. C. Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. Cancer Res. 70, 2115–2125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Teng, M., Zhou, S., Cai, C., Lupien, M. & He, H. H. Pioneer of prostate cancer: past, present and the future of FOXA1. Protein Cell 12, 29–38 (2021).

    Article  CAS  PubMed  Google Scholar 

  76. Tiwari, N. et al. Klf4 is a transcriptional regulator of genes critical for EMT, including Jnk1 (Mapk8). PLoS ONE 8, e57329 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Agbo, K. C. et al. Loss of the Kruppel-like factor 4 tumor suppressor is associated with epithelial-mesenchymal transition in colorectal cancer. J. Cancer Metastasis Treat. https://doi.org/10.20517/2394-4722.2019.35 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Zeisberg, E. M., Potenta, S., Xie, L., Zeisberg, M. & Kalluri, R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67, 10123–10128 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Pardali, E., Sanchez-Duffhues, G., Gomez-Puerto, M. C. & Ten Dijke, P. TGF-β-induced endothelial–mesenchymal transition in fibrotic diseases. Int. J. Mol. Sci. https://doi.org/10.3390/ijms18102157 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Zeisberg, E. M., Potenta, S. E., Sugimoto, H., Zeisberg, M. & Kalluri, R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J. Am. Soc. Nephrol. 19, 2282–2287 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13, 952–961 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Tombor, L. S. et al. Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction. Nat. Commun. 12, 681 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lin, S. C. et al. Endothelial-to-osteoblast conversion generates osteoblastic metastasis of prostate cancer. Dev. Cell 41, 467–480 e463 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Medici, D. et al. Conversion of vascular endothelial cells into multipotent stem-like cells. Nat. Med. 16, 1400–1406 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  86. Acloque, H., Adams, M. S., Fishwick, K., Bronner-Fraser, M. & Nieto, M. A. Epithelial–mesenchymal transitions: the importance of changing cell state in development and disease. J. Clin. Invest. 119, 1438–1449 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sanchez-Martin, M. et al. SLUG (SNAI2) deletions in patients with Waardenburg disease. Hum. Mol. Genet. 11, 3231–3236 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Zweier, C. et al. “Mowat-Wilson” syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies–mental retardation syndrome caused by mutations in the zinc finger homeo Box 1B gene. Am. J. Med. Genet. 108, 177–181 (2002).

    Article  PubMed  Google Scholar 

  89. el Ghouzzi, V. et al. Mutations of the TWIST gene in the Saethre–Chotzen syndrome. Nat. Genet. 15, 42–46 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Howard, T. D. et al. Mutations in TWIST, a basic helix–loop–helix transcription factor, in Saethre–Chotzen syndrome. Nat. Genet. 15, 36–41 (1997).

    Article  PubMed  Google Scholar 

  91. Horiguchi, K. et al. Role of Ras signaling in the induction of snail by transforming growth factor-β. J. Biol. Chem. 284, 245–253 (2009).

    Article  CAS  PubMed  Google Scholar 

  92. Wang, Y. et al. Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells. Oncogene 29, 4658–4670 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zhang, X., Cheng, Q., Yin, H. & Yang, G. Regulation of autophagy and EMT by the interplay between p53 and RAS during cancer progression [Review]. Int. J. Oncol. 51, 18–24 (2017).

    Article  CAS  PubMed  Google Scholar 

  94. Pylayeva-Gupta, Y., Grabocka, E. & Bar-Sagi, D. RAS oncogenes: weaving a tumorigenic web. Nat. Rev. Cancer 11, 761–774 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bisogno, L. S., Friedersdorf, M. B. & Keene, J. D. Ras post-transcriptionally enhances a pre-malignantly primed EMT to promote invasion. iScience 4, 97–108 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yoh, K. E. et al. Repression of p63 and induction of EMT by mutant Ras in mammary epithelial cells. Proc. Natl Acad. Sci. USA 113, E6107–E6116 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Grassian, A. R. et al. Isocitrate dehydrogenase (IDH) mutations promote a reversible ZEB1/microRNA (miR)-200-dependent epithelial–mesenchymal transition (EMT). J. Biol. Chem. 287, 42180–42194 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lu, J. et al. IDH1 mutation promotes proliferation and migration of glioma cells via EMT induction. J. BUON 24, 2458–2464 (2019).

    PubMed  Google Scholar 

  99. Jiang, Z. et al. RB1 and p53 at the crossroad of EMT and triple-negative breast cancer. Cell Cycle 10, 1563–1570 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Fedele, V. & Melisi, D. Permissive state of EMT: the role of immune cell compartment. Front. Oncol. 10, 587 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Quaresma, M. C. et al. Mutant CFTR drives TWIST1 mediated epithelial–mesenchymal transition. Cell Death Dis. 11, 920 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Gibson, R. L., Burns, J. L. & Ramsey, B. W. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am. J. Respir. Crit. Care Med. 168, 918–951 (2003).

    Article  PubMed  Google Scholar 

  103. Nichols, D., Chmiel, J. & Berger, M. Chronic inflammation in the cystic fibrosis lung: alterations in inter- and intracellular signaling. Clin. Rev. Allergy Immunol. 34, 146–162 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Worlitzsch, D. et al. Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J. Clin. Invest. 109, 317–325 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Harris, W. T. et al. Plasma TGF-β1 in pediatric cystic fibrosis: potential biomarker of lung disease and response to therapy. Pediatr. Pulmonol. 46, 688–695 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Wellenstein, M. D. & de Visser, K. E. Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape. Immunity 48, 399–416 (2018).

    Article  CAS  PubMed  Google Scholar 

  107. Dai, Y. et al. Copy number gain of ZEB1 mediates a double-negative feedback loop with miR-33a-5p that regulates EMT and bone metastasis of prostate cancer dependent on TGF-β signaling. Theranostics 9, 6063–6079 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Berenguer, J. & Celia-Terrassa, T. Cell memory of epithelial–mesenchymal plasticity in cancer. Curr. Opin. Cell Biol. 69, 103–110 (2021).

    Article  CAS  PubMed  Google Scholar 

  109. Ewing, J. A. V. I. I. On the production of transient electric currents in iron and steel conductors by twisting them when magnetised or by magnetising them when twisted. Proc. R. Soc. Lond. 33, 21–23 (1882).

    Article  Google Scholar 

  110. Ferrell, J. E. Jr Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr. Opin. Cell Biol. 14, 140–148 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Gregory, P. A. et al. An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial–mesenchymal transition. Mol. Biol. Cell 22, 1686–1698 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jain, P. et al. Epigenetic memory acquired during long-term EMT induction governs the recovery to the epithelial state. J. R. Soc. Interface 20, 20220627 (2023).

    Article  CAS  PubMed  Google Scholar 

  113. Stylianou, N. et al. A molecular portrait of epithelial–mesenchymal plasticity in prostate cancer associated with clinical outcome. Oncogene 38, 913–934 (2019).

    Article  CAS  PubMed  Google Scholar 

  114. Celia-Terrassa, T. et al. Hysteresis control of epithelial–mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability. Nat. Commun. 9, 5005 (2018). This study shows direct evidence for hysteresis, and its functional consequences, in EMT by uncoupling the miR-200–ZEB negative feedback loop.

    Article  PubMed  PubMed Central  Google Scholar 

  115. 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).

    Article  CAS  PubMed  Google Scholar 

  116. Sarrio, D., Franklin, C. K., Mackay, A., Reis-Filho, J. S. & Isacke, C. M. Epithelial and mesenchymal subpopulations within normal basal breast cell lines exhibit distinct stem cell/progenitor properties. Stem Cell 30, 292–303 (2012).

    Article  CAS  Google Scholar 

  117. Harner-Foreman, N. et al. 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 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ruscetti, M. et al. HDAC inhibition impedes epithelial–mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer. Oncogene 35, 3781–3795 (2016).

    Article  CAS  PubMed  Google Scholar 

  119. Mathis, R. A., Sokol, E. S. & Gupta, P. B. Cancer cells exhibit clonal diversity in phenotypic plasticity. Open. Biol. https://doi.org/10.1098/rsob.160283 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  121. Bhatia, S. et al. Interrogation of phenotypic plasticity between epithelial and mesenchymal states in breast cancer. J. Clin. Med. https://doi.org/10.3390/jcm8060893 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Neelakantan, D. et al. EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells. Nat. Commun. 8, 15773 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Lan, L. et al. GREM1 is required to maintain cellular heterogeneity in pancreatic cancer. Nature https://doi.org/10.1038/s41586-022-04888-7 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Boareto, M. et al. Notch–Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype. J. R. Soc. Interface https://doi.org/10.1098/rsif.2015.1106 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Jain, P., Bhatia, S., Thompson, E. W. & Jolly, M. K. Population dynamics of epithelial–mesenchymal heterogeneity in cancer cells. Biomolecules https://doi.org/10.3390/biom12030348 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Tripathi, S., Chakraborty, P., Levine, H. & Jolly, M. K. A mechanism for epithelial–mesenchymal heterogeneity in a population of cancer cells. PLoS Comput. Biol. 16, e1007619 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Elowitz, M. B., Levine, A. J., Siggia, E. D. & Swain, P. S. Stochastic gene expression in a single cell. Science 297, 1183–1186 (2002).

    Article  CAS  PubMed  Google Scholar 

  129. McAdams, H. H. & Arkin, A. Stochastic mechanisms in gene expression. Proc. Natl Acad. Sci. USA 94, 814–819 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Losick, R. & Desplan, C. Stochasticity and cell fate. Science 320, 65–68 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Jia, W. et al. Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT. Oncotarget 11, 2611–2624 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Desai, R. V. et al. A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions. Science https://doi.org/10.1126/science.abc6506 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Wang, Q., Holmes, W. R., Sosnik, J., Schilling, T. & Nie, Q. Cell sorting and noise-induced cell plasticity coordinate to sharpen boundaries between gene expression domains. PLoS Comput. Biol. 13, e1005307 (2017). Using computational modelling, this study proposes that boundary sharpening during developmental segmentation depends on adhesion-based and repulsion-based cell sorting, as well as noise-induced cell state transitions.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Wellens, T., Shatokhin, V. & Buchleitner, A. Stochastic resonance. Rep. Prog. Phys. 67, 45 (2003).

    Article  Google Scholar 

  135. Matak, A. et al. Stochastic phenotype switching leads to intratumor heterogeneity in human liver cancer. Hepatology 68, 933–948 (2018).

    Article  CAS  PubMed  Google Scholar 

  136. Sosnik, J. et al. Noise modulation in retinoic acid signaling sharpens segmental boundaries of gene expression in the embryonic zebrafish hindbrain. eLife 5, e14034 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Zhang, L. et al. Noise drives sharpening of gene expression boundaries in the zebrafish hindbrain. Mol. Syst. Biol. 8, 613 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Chang, H. H., Hemberg, M., Barahona, M., Ingber, D. E. & Huang, S. Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature 453, 544–547 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Eldar, A. & Elowitz, M. B. Functional roles for noise in genetic circuits. Nature 467, 167–173 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Pujadas, E. & Feinberg, A. P. Regulated noise in the epigenetic landscape of development and disease. Cell 148, 1123–1131 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ozbudak, E. M., Thattai, M., Kurtser, I., Grossman, A. D. & van Oudenaarden, A. Regulation of noise in the expression of a single gene. Nat. Genet. 31, 69–73 (2002).

    Article  CAS  PubMed  Google Scholar 

  142. Battich, N., Stoeger, T. & Pelkmans, L. Control of transcript variability in single mammalian cells. Cell 163, 1596–1610 (2015).

    Article  CAS  PubMed  Google Scholar 

  143. Arias, A. M. & Hayward, P. Filtering transcriptional noise during development: concepts and mechanisms. Nat. Rev. Genet. 7, 34–44 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Bahar, R. et al. Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441, 1011–1014 (2006).

    Article  CAS  PubMed  Google Scholar 

  145. Kussell, E. & Leibler, S. Phenotypic diversity, population growth, and information in fluctuating environments. Science 309, 2075–2078 (2005).

    Article  CAS  PubMed  Google Scholar 

  146. Acar, M., Mettetal, J. T. & van Oudenaarden, A. Stochastic switching as a survival strategy in fluctuating environments. Nat. Genet. 40, 471–475 (2008).

    Article  CAS  PubMed  Google Scholar 

  147. Boulay, J. L., Dennefeld, C. & Alberga, A. The Drosophila developmental gene snail encodes a protein with nucleic acid binding fingers. Nature 330, 395–398 (1987).

    Article  CAS  PubMed  Google Scholar 

  148. Thisse, B., Stoetzel, C., Gorostiza-Thisse, C. & Perrin-Schmitt, F. Sequence of the twist gene and nuclear localization of its protein in endomesodermal cells of early Drosophila embryos. EMBO J. 7, 2175–2183 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Nieto, M. A., Bennett, M. F., Sargent, M. G. & Wilkinson, D. G. Cloning and developmental expression of Sna, a murine homologue of the Drosophila snail gene. Development 116, 227–237 (1992).

    Article  CAS  PubMed  Google Scholar 

  150. Funahashi, J., Sekido, R., Murai, K., Kamachi, Y. & Kondoh, H. δ-Crystallin enhancer binding protein δEF1 is a zinc finger-homeodomain protein implicated in postgastrulation embryogenesis. Development 119, 433–446 (1993).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  152. Verschueren, K. et al. SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5′-CACCT sequences in candidate target genes. J. Biol. Chem. 274, 20489–20498 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  154. Savagner, P., Yamada, K. M. & Thiery, J. P. The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial–mesenchymal transition. J. Cell Biol. 137, 1403–1419 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Grooteclaes, M. L. & Frisch, S. M. Evidence for a function of CtBP in epithelial gene regulation and anoikis. Oncogene 19, 3823–3828 (2000).

    Article  CAS  PubMed  Google Scholar 

  156. Comijn, J. et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol. Cell 7, 1267–1278 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  159. Oba, S. et al. miR-200b precursor can ameliorate renal tubulointerstitial fibrosis. PLoS ONE 5, e13614 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Kida, Y., Asahina, K., Teraoka, H., Gitelman, I. & Sato, T. Twist relates to tubular epithelial–mesenchymal transition and interstitial fibrogenesis in the obstructed kidney. J. Histochem. Cytochem. 55, 661–673 (2007).

    Article  CAS  PubMed  Google Scholar 

  162. Grande, M. T. et al. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat. Med. 21, 989–997 (2015). In this study, Snai1 reactivation in tubular epithelial cells is shown to induce a partial EMT, which indirectly promotes myofibroblast formation and fibrinogenesis.

    Article  CAS  PubMed  Google Scholar 

  163. Hajra, K. M., Chen, D. Y. & Fearon, E. R. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 62, 1613–1618 (2002).

    CAS  PubMed  Google Scholar 

  164. Vesuna, F., van Diest, P., Chen, J. H. & Raman, V. Twist is a transcriptional repressor of E-cadherin gene expression in breast cancer. Biochem. Biophys. Res. Commun. 367, 235–241 (2008).

    Article  CAS  PubMed  Google Scholar 

  165. Lehmann, W. et al. ZEB1 turns into a transcriptional activator by interacting with YAP1 in aggressive cancer types. Nat. Commun. 7, 10498 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Mani, S. A. et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc. Natl Acad. Sci. USA 104, 10069–10074 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Hartwell, K. A. et al. The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proc. Natl Acad. Sci. USA 103, 18969–18974 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Wang, X. et al. Kruppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Res. 67, 7184–7193 (2007).

    Article  CAS  PubMed  Google Scholar 

  169. Takano, S. et al. Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization. Genes Dev. 30, 233–247 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  171. Tavares, A. L. P., Brown, J. A., Ulrich, E. C., Dvorak, K. & Runyan, R. B. Runx2-I is an early regulator of epithelial–mesenchymal cell transition in the chick embryo. Dev. Dyn. 247, 542–554 (2018).

    Article  CAS  PubMed  Google Scholar 

  172. McCoy, E. L. et al. Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial–mesenchymal transition. J. Clin. Invest. 119, 2663–2677 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Perez-Moreno, M. A. et al. A new role for E12/E47 in the repression of E-cadherin expression and epithelial–mesenchymal transitions. J. Biol. Chem. 276, 27424–27431 (2001).

    Article  CAS  PubMed  Google Scholar 

  174. Sobrado, V. R. et al. The class I bHLH factors E2-2A and E2-2B regulate EMT. J. Cell Sci. 122, 1014–1024 (2009).

    Article  CAS  PubMed  Google Scholar 

  175. Stemmler, M. P., Eccles, R. L., Brabletz, S. & Brabletz, T. Non-redundant functions of EMT transcription factors. Nat. Cell Biol. 21, 102–112 (2019). This review discusses the specific, distinct functions of the core EMT-TFs.

    Article  CAS  PubMed  Google Scholar 

  176. Goossens, S., Vandamme, N., Van Vlierberghe, P. & Berx, G. EMT transcription factors in cancer development re-evaluated: beyond EMT and MET. Biochim. Biophys. Acta Rev. Cancer 1868, 584–591 (2017).

    Article  CAS  PubMed  Google Scholar 

  177. Nieto, M. A. The snail superfamily of zinc-finger transcription factors. Nat. Rev. Mol. Cell Biol. 3, 155–166 (2002).

    Article  CAS  PubMed  Google Scholar 

  178. Skrypek, N., Goossens, S., De Smedt, E., Vandamme, N. & Berx, G. Epithelial-to-mesenchymal transition: epigenetic reprogramming driving cellular plasticity. Trends Genet. 33, 943–959 (2017).

    Article  CAS  PubMed  Google Scholar 

  179. Kang, E., Seo, J., Yoon, H. & Cho, S. The post-translational regulation of epithelial–mesenchymal transition-inducing transcription factors in cancer metastasis. Int. J. Mol. Sci. https://doi.org/10.3390/ijms22073591 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  180. 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).

    Article  CAS  PubMed  Google Scholar 

  181. Park, S. M., Gaur, A. B., Lengyel, E. & Peter, M. E. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22, 894–907 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. 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).

    Article  CAS  PubMed  Google Scholar 

  184. Lu, M., Jolly, M. K., Levine, H., Onuchic, J. N. & Ben-Jacob, E. microRNA-based regulation of epithelial–hybrid–mesenchymal fate determination. Proc. Natl Acad. Sci. USA 110, 18144–18149 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Zhang, J. et al. TGF-β-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci. Signal. 7, ra91 (2014).

    Article  PubMed  Google Scholar 

  186. Tian, X. J., Zhang, H. & Xing, J. Coupled reversible and irreversible bistable switches underlying TGFβ-induced epithelial to mesenchymal transition. Biophys. J. 105, 1079–1089 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Liu, Y. et al. Competitive endogenous RNA is an intrinsic component of EMT regulatory circuits and modulates EMT. Nat. Commun. 10, 1637 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Salmena, L., Poliseno, L., Tay, Y., Kats, L. & Pandolfi, P. P. A ceRNA hypothesis: the Rosetta stone of a hidden RNA language. Cell 146, 353–358 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Gantier, M. P. et al. Analysis of microRNA turnover in mammalian cells following Dicer1 ablation. Nucleic Acids Res. 39, 5692–5703 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Bosson, A. D., Zamudio, J. R. & Sharp, P. A. Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition. Mol. Cell 56, 347–359 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Jansson, M. D. & Lund, A. H. microRNA and cancer. Mol. Oncol. 6, 590–610 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Cheng, J. T. et al. Insights into biological role of lncRNAs in epithelial–mesenchymal transition. Cells https://doi.org/10.3390/cells8101178 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  193. O’Brien, S. J. et al. Long non-coding RNA (lncRNA) and epithelial–mesenchymal transition (EMT) in colorectal cancer: a systematic review. Cancer Biol. Ther. 21, 769–781 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Zhang, J. et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteom. Bioinforma. 13, 17–24 (2015).

    Article  CAS  Google Scholar 

  195. Dragomir, M., Chen, B. & Calin, G. A. Exosomal lncRNAs as new players in cell-to-cell communication. Transl. Cancer Res. 7, S243–S252 (2018).

    Article  CAS  PubMed  Google Scholar 

  196. Zhang, X. et al. Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT. Mol. Cancer 18, 40 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Li, Z. et al. Tumor-derived exosomal lnc-Sox2ot promotes EMT and stemness by acting as a ceRNA in pancreatic ductal adenocarcinoma. Oncogene 37, 3822–3838 (2018).

    Article  CAS  PubMed  Google Scholar 

  198. Wang, X. et al. Melittin-induced long non-coding RNA NONHSAT105177 inhibits proliferation and migration of pancreatic ductal adenocarcinoma. Cell Death Dis. 9, 940 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Pan, L. et al. Exosomes-mediated transfer of long noncoding RNA ZFAS1 promotes gastric cancer progression. J. Cancer Res. Clin. Oncol. 143, 991–1004 (2017).

    Article  CAS  PubMed  Google Scholar 

  200. Wu, D. M. et al. TGF-β-mediated exosomal lnc-MMP2-2 regulates migration and invasion of lung cancer cells to the vasculature by promoting MMP2 expression. Cancer Med. 7, 5118–5129 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Xue, M. et al. Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1. Mol. Cancer 16, 143 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Javaid, S. et al. Dynamic chromatin modification sustains epithelial–mesenchymal transition following inducible expression of Snail-1. Cell Rep. 5, 1679–1689 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Graff, J. R., Gabrielson, E., Fujii, H., Baylin, S. B. & Herman, J. G. Methylation patterns of the E-cadherin 5′ CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J. Biol. Chem. 275, 2727–2732 (2000).

    Article  CAS  PubMed  Google Scholar 

  204. Cheng, C. W. et al. Mechanisms of inactivation of E-cadherin in breast carcinoma: modification of the two-hit hypothesis of tumor suppressor gene. Oncogene 20, 3814–3823 (2001).

    Article  CAS  PubMed  Google Scholar 

  205. Lombaerts, M. et al. E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br. J. Cancer 94, 661–671 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Chen, Y., Wang, K., Qian, C. N. & Leach, R. DNA methylation is associated with transcription of Snail and Slug genes. Biochem. Biophys. Res. Commun. 430, 1083–1090 (2013).

    Article  CAS  PubMed  Google Scholar 

  207. Galvan, J. A. et al. TWIST1 and TWIST2 promoter methylation and protein expression in tumor stroma influence the epithelial–mesenchymal transition-like tumor budding phenotype in colorectal cancer. Oncotarget 6, 874–885 (2015).

    Article  PubMed  Google Scholar 

  208. Alghamian, Y., Soukkarieh, C., Abbady, A. Q. & Murad, H. Investigation of role of CpG methylation in some epithelial mesenchymal transition gene in a chemoresistant ovarian cancer cell line. Sci. Rep. 12, 7494 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Vrba, L. et al. Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. PLoS ONE 5, e8697 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Wiklund, E. D. et al. Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int. J. Cancer 128, 1327–1334 (2011).

    Article  CAS  PubMed  Google Scholar 

  211. Davalos, V. et al. Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis. Oncogene 31, 2062–2074 (2012).

    Article  CAS  PubMed  Google Scholar 

  212. Tellez, C. S. et al. EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells. Cancer Res. 71, 3087–3097 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Dang, T. T., Esparza, M. A., Maine, E. A., Westcott, J. M. & Pearson, G. W. DeltaNp63α promotes breast cancer cell motility through the selective activation of components of the epithelial-to-mesenchymal transition program. Cancer Res. 75, 3925–3935 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Abell, A. N. et al. MAP3K4/CBP-regulated H2B acetylation controls epithelial–mesenchymal transition in trophoblast stem cells. Cell Stem Cell 8, 525–537 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Warzecha, C. C., Sato, T. K., Nabet, B., Hogenesch, J. B. & Carstens, R. P. ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Mol. Cell 33, 591–601 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Segelle, A. et al. Histone marks regulate the epithelial-to-mesenchymal transition via alternative splicing. Cell Rep. 38, 110357 (2022). This study illustrates how histone modifications can interact with splicing regulators, consequently driving alternative splicing programmes that underlie EMTs.

    Article  CAS  PubMed  Google Scholar 

  217. Sahu, S. K. et al. A complex epigenome-splicing crosstalk governs epithelial-to-mesenchymal transition in metastasis and brain development. Nat. Cell Biol. 24, 1265–1277 (2022).

    Article  CAS  PubMed  Google Scholar 

  218. Gomes, A. P. et al. Dynamic incorporation of histone H3 variants into chromatin is essential for acquisition of aggressive traits and metastatic colonization. Cancer Cell 36, 402–417.e13 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Hodge, D. Q., Cui, J., Gamble, M. J. & Guo, W. Histone variant macroH2A1 plays an isoform-specific role in suppressing epithelial–mesenchymal transition. Sci. Rep. 8, 841 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Dumont, N. et al. Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers. Proc. Natl Acad. Sci. USA 105, 14867–14872 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Galle, E. et al. DNA methylation-driven EMT is a common mechanism of resistance to various therapeutic agents in cancer. Clin. Epigenetics 12, 27 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Jia, W., Deshmukh, A., Mani, S. A., Jolly, M. K. & Levine, H. A possible role for epigenetic feedback regulation in the dynamics of the epithelial–mesenchymal transition (EMT). Phys. Biol. 16, 066004 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Yuan, S. et al. Global regulation of the histone mark H3K36me2 underlies epithelial plasticity and metastatic progression. Cancer Discov. 10, 854–871 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Morin, C., Moyret-Lalle, C., Mertani, H. C., Diaz, J. J. & Marcel, V. Heterogeneity and dynamic of EMT through the plasticity of ribosome and mRNA translation. Biochim. Biophys. Acta Rev. Cancer 1877, 188718 (2022).

    Article  CAS  PubMed  Google Scholar 

  225. Willig, T. N. et al. Mutations in ribosomal protein S19 gene and Diamond Blackfan anemia: wide variations in phenotypic expression. Blood 94, 4294–4306 (1999).

    CAS  PubMed  Google Scholar 

  226. Boria, I. et al. The ribosomal basis of Diamond–Blackfan anemia: mutation and database update. Hum. Mutat. 31, 1269–1279 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Lipton, J. M. & Ellis, S. R. Diamond–Blackfan anemia: diagnosis, treatment, and molecular pathogenesis. Hematol. Oncol. Clin. North. Am. 23, 261–282 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Dauwerse, J. G. et al. Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nat. Genet. 43, 20–22 (2011).

    Article  CAS  PubMed  Google Scholar 

  229. Valdez, B. C., Henning, D., So, R. B., Dixon, J. & Dixon, M. J. The Treacher Collins syndrome (TCOF1) gene product is involved in ribosomal DNA gene transcription by interacting with upstream binding factor. Proc. Natl Acad. Sci. USA 101, 10709–10714 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Wielosz, E., Dryglewska, M. & Majdan, M. Clinical consequences of the presence of anti-RNA Pol III antibodies in systemic sclerosis. Postepy Dermatol. Alergol. 37, 909–914 (2020).

    Article  PubMed  Google Scholar 

  231. Ochs, R. L., Lischwe, M. A., Spohn, W. H. & Busch, H. Fibrillarin: a new protein of the nucleolus identified by autoimmune sera. Biol. Cell 54, 123–133 (1985).

    Article  CAS  PubMed  Google Scholar 

  232. Arnett, F. C. et al. Autoantibodies to fibrillarin in systemic sclerosis (scleroderma). An immunogenetic, serologic, and clinical analysis. Arthritis Rheum. 39, 1151–1160 (1996).

    Article  CAS  PubMed  Google Scholar 

  233. Bassler, J. & Hurt, E. Eukaryotic ribosome assembly. Annu. Rev. Biochem. 88, 281–306 (2019).

    Article  CAS  PubMed  Google Scholar 

  234. Benyelles, M. et al. NHP2 deficiency impairs rRNA biogenesis and causes pulmonary fibrosis and Hoyeraal–Hreidarsson syndrome. Hum. Mol. Genet. 29, 907–922 (2020).

    Article  CAS  PubMed  Google Scholar 

  235. Freed, E. F. & Baserga, S. J. The C-terminus of Utp4, mutated in childhood cirrhosis, is essential for ribosome biogenesis. Nucleic Acids Res. 38, 4798–4806 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Freed, E. F., Prieto, J. L., McCann, K. L., McStay, B. & Baserga, S. J. NOL11, implicated in the pathogenesis of North American Indian childhood cirrhosis, is required for pre-rRNA transcription and processing. PLoS Genet. 8, e1002892 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Thorolfsdottir, R. B. et al. Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation. Commun. Biol. 1, 68 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  238. Prakash, V. et al. Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease. Nat. Commun. 10, 2110 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Hou, Y. et al. Airway basal cells mediate hypoxia-induced EMT by increasing ribosome biogenesis. Front. Pharmacol. 12, 783946 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Ito, N. et al. Ribosome incorporation into somatic cells promotes lineage transdifferentiation towards multipotency. Sci. Rep. 8, 1634 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  241. Kudo, M. et al. Ribosome incorporation induces EMT-like phenomenon with cell cycle arrest in human breast cancer cell. Cell Tissues Organs 211, 212–221 (2022).

    Article  CAS  Google Scholar 

  242. Mili, S., Moissoglu, K. & Macara, I. G. Genome-wide screen reveals APC-associated RNAs enriched in cell protrusions. Nature 453, 115–119 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Mardakheh, F. K. et al. Global analysis of mRNA, translation, and protein localization: local translation is a key regulator of cell protrusions. Dev. Cell 35, 344–357 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Wang, X. et al. Methyltransferase like 13 mediates the translation of Snail in head and neck squamous cell carcinoma. Int. J. Oral. Sci. 13, 26 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  245. Dermit, M. et al. Subcellular mRNA localization regulates ribosome biogenesis in migrating cells. Dev. Cell 55, 298–313 e210 (2020). This article reveals how cellular protrusions formed during EMT act as hot spots for RP-coding RNA translation, enhancing ribosome biogenesis and overall protein synthesis in migratory cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Lin, X. et al. RNA m6A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat. Commun. 10, 2065 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  247. Chaudhury, A. et al. CELF1 is a central node in post-transcriptional regulatory programmes underlying EMT. Nat. Commun. 7, 13362 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Evdokimova, V. et al. Translational activation of snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelial–mesenchymal transition. Cancer Cell 15, 402–415 (2009).

    Article  CAS  PubMed  Google Scholar 

  249. Gulhati, P. et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 71, 3246–3256 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Cai, W., Ye, Q. & She, Q. B. Loss of 4E-BP1 function induces EMT and promotes cancer cell migration and invasion via cap-dependent translational activation of snail. Oncotarget 5, 6015–6027 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  251. Azmi, A. S. et al. Targeting the nuclear export protein XPO1/CRM1 reverses epithelial to mesenchymal transition. Sci. Rep. 5, 16077 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  252. Kang, H., Kim, H., Lee, S., Youn, H. & Youn, B. Role of metabolic reprogramming in epithelial–mesenchymal transition (EMT). Int. J. Mol. Sci. https://doi.org/10.3390/ijms20082042 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  253. Georgakopoulos-Soares, I., Chartoumpekis, D. V., Kyriazopoulou, V. & Zaravinos, A. EMT factors and metabolic pathways in cancer. Front. Oncol. 10, 499 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  254. Sciacovelli, M. & Frezza, C. Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer. FEBS J. 284, 3132–3144 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Hua, W., Ten Dijke, P., Kostidis, S., Giera, M. & Hornsveld, M. TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer. Cell Mol. Life Sci. 77, 2103–2123 (2020).

    Article  CAS  PubMed  Google Scholar 

  256. Cha, Y. H., Yook, J. I., Kim, H. S. & Kim, N. H. Catabolic metabolism during cancer EMT. Arch. Pharm. Res. 38, 313–320 (2015).

    Article  CAS  PubMed  Google Scholar 

  257. Swinnen, J. V., Brusselmans, K. & Verhoeven, G. Increased lipogenesis in cancer cells: new players, novel targets. Curr. Opin. Clin. Nutr. Metab. Care 9, 358–365 (2006).

    Article  CAS  PubMed  Google Scholar 

  258. Kuhajda, F. P. Fatty acid synthase and cancer: new application of an old pathway. Cancer Res. 66, 5977–5980 (2006).

    Article  CAS  PubMed  Google Scholar 

  259. Zhu, Y. et al. Posttranslational control of lipogenesis in the tumor microenvironment. J. Hematol. Oncol. 15, 120 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Singh, R., Yadav, V., Kumar, S. & Saini, N. microRNA-195 inhibits proliferation, invasion and metastasis in breast cancer cells by targeting FASN, HMGCR, ACACA and CYP27B1. Sci. Rep. 5, 17454 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Gong, J. et al. Inhibition of FASN suppresses migration, invasion and growth in hepatoma carcinoma cells by deregulating the HIF-1α/IGFBP1 pathway. Int. J. Oncol. 50, 883–892 (2017).

    Article  CAS  PubMed  Google Scholar 

  262. Jiang, L. et al. Up-regulated FASN expression promotes transcoelomic metastasis of ovarian cancer cell through epithelial–mesenchymal transition. Int. J. Mol. Sci. 15, 11539–11554 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  263. Sun, L. et al. Small interfering RNA-mediated knockdown of fatty acid synthase attenuates the proliferation and metastasis of human gastric cancer cells via the mTOR/Gli1 signaling pathway. Oncol. Lett. 16, 594–602 (2018).

    PubMed  PubMed Central  Google Scholar 

  264. Yang, L. et al. A FASN-TGF-β1-FASN regulatory loop contributes to high EMT/metastatic potential of cisplatin-resistant non-small cell lung cancer. Oncotarget 7, 55543–55554 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  265. Gonzalez-Guerrico, A. M. et al. Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer. Oncotarget 7, 71151–71168 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  266. Chen, Y. et al. ZEB1 regulates multiple oncogenic components involved in uveal melanoma progression. Sci. Rep. 7, 45 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  267. Hung, C. M. et al. Osthole suppresses hepatocyte growth factor (HGF)-induced epithelial–mesenchymal transition via repression of the c-Met/Akt/mTOR pathway in human breast cancer cells. J. Agric. Food Chem. 59, 9683–9690 (2011).

    Article  CAS  PubMed  Google Scholar 

  268. Angelucci, C. et al. Epithelial–stromal interactions in human breast cancer: effects on adhesion, plasma membrane fluidity and migration speed and directness. PLoS ONE 7, e50804 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Edmond, V. et al. Downregulation of ceramide synthase-6 during epithelial-to-mesenchymal transition reduces plasma membrane fluidity and cancer cell motility. Oncogene 34, 996–1005 (2015).

    Article  CAS  PubMed  Google Scholar 

  270. Taraboletti, G. et al. Membrane fluidity affects tumor-cell motility, invasion and lung-colonizing potential. Int. J. Cancer 44, 707–713 (1989).

    Article  CAS  PubMed  Google Scholar 

  271. Zhao, W. et al. Candidate antimetastasis drugs suppress the metastatic capacity of breast cancer cells by reducing membrane fluidity. Cancer Res. 76, 2037–2049 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Wang, Y. et al. NNMT contributes to high metastasis of triple negative breast cancer by enhancing PP2A/MEK/ERK/c-Jun/ABCA1 pathway mediated membrane fluidity. Cancer Lett. 547, 215884 (2022).

    Article  CAS  PubMed  Google Scholar 

  273. Eiriksson, F. F. et al. Altered plasmalogen content and fatty acid saturation following epithelial to mesenchymal transition in breast epithelial cell lines. Int. J. Biochem. Cell Biol. 103, 99–104 (2018).

    Article  CAS  PubMed  Google Scholar 

  274. Yu, H., Duan, P., Zhu, H. & Rao, D. miR-613 inhibits bladder cancer proliferation and migration through targeting SphK1. Am. J. Transl. Res. 9, 1213–1221 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  275. Fan, Z., Jiang, H., Wang, Z. & Qu, J. Atorvastatin partially inhibits the epithelial–mesenchymal transition in A549 cells induced by TGF-β1 by attenuating the upregulation of SphK1. Oncol. Rep. 36, 1016–1022 (2016).

    Article  CAS  PubMed  Google Scholar 

  276. Long, J., Xie, Y., Yin, J., Lu, W. & Fang, S. SphK1 promotes tumor cell migration and invasion in colorectal cancer. Tumour Biol. 37, 6831–6836 (2016).

    Article  CAS  PubMed  Google Scholar 

  277. Liu, H., Ma, Y., He, H. W., Zhao, W. L. & Shao, R. G. SPHK1 (sphingosine kinase 1) induces epithelial–mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells. Autophagy 13, 900–913 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Xu, C. Y. et al. SphK1 modulates cell migration and EMT-related marker expression by regulating the expression of p-FAK in colorectal cancer cells. Int. J. Mol. Med. 39, 1277–1284 (2017).

    Article  CAS  PubMed  Google Scholar 

  279. Meshcheryakova, A. et al. Exploring the role of sphingolipid machinery during the epithelial to mesenchymal transition program using an integrative approach. Oncotarget 7, 22295–22323 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  280. Zeng, Y. et al. Sphingosine-1-phosphate induced epithelial–mesenchymal transition of hepatocellular carcinoma via an MMP-7/ syndecan-1/TGF-β autocrine loop. Oncotarget 7, 63324–63337 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  281. Ishizawa, S. et al. Sphingosine-1-phosphate induces differentiation of cultured renal tubular epithelial cells under Rho kinase activation via the S1P2 receptor. Clin. Exp. Nephrol. 18, 844–852 (2014).

    Article  CAS  PubMed  Google Scholar 

  282. Zeng, Y. E., Yao, X. H., Yan, Z. P., Liu, J. X. & Liu, X. H. Potential signaling pathway involved in sphingosine-1-phosphate-induced epithelial–mesenchymal transition in cancer. Oncol. Lett. 12, 379–382 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Fajardo, V. A., McMeekin, L. & LeBlanc, P. J. Influence of phospholipid species on membrane fluidity: a meta-analysis for a novel phospholipid fluidity index. J. Membr. Biol. 244, 97–103 (2011).

    Article  CAS  PubMed  Google Scholar 

  284. Ruiz, M. et al. Sphingosine 1-phosphate mediates adiponectin receptor signaling essential for lipid homeostasis and embryogenesis. Nat. Commun. 13, 7162 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Lu, P., White-Gilbertson, S., Nganga, R., Kester, M. & Voelkel-Johnson, C. Expression of the SNAI2 transcriptional repressor is regulated by C16-ceramide. Cancer Biol. Ther. 20, 922–930 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Prijic, S. & Chang, J. T. ABCA1 expression is upregulated in an EMT in breast cancer cell lines via MYC-mediated de-repression of its proximal ebox element. Biomedicines https://doi.org/10.3390/biomedicines10030581 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  287. Alonso, A. & Goni, F. M. The physical properties of ceramides in membranes. Annu. Rev. Biophys. 47, 633–654 (2018).

    Article  CAS  PubMed  Google Scholar 

  288. van Blitterswijk, W. J., van der Meer, B. W. & Hilkmann, H. Quantitative contributions of cholesterol and the individual classes of phospholipids and their degree of fatty acyl (un)saturation to membrane fluidity measured by fluorescence polarization. Biochemistry 26, 1746–1756 (1987).

    Article  PubMed  Google Scholar 

  289. Dalmau, N., Jaumot, J., Tauler, R. & Bedia, C. Epithelial-to-mesenchymal transition involves triacylglycerol accumulation in DU145 prostate cancer cells. Mol. Biosyst. 11, 3397–3406 (2015).

    Article  CAS  PubMed  Google Scholar 

  290. Lin, S. J., Yang, D. R., Li, G. & Chang, C. TR4 nuclear receptor different roles in prostate cancer progression. Front. Endocrinol. 6, 78 (2015).

    Article  Google Scholar 

  291. Xu, X. et al. VSP-17 suppresses the migration and invasion of triple-negative breast cancer cells through inhibition of the EMT process via the PPARγ/AMPK signaling pathway. Oncol. Rep. 45, 975–986 (2021).

    Article  CAS  PubMed  Google Scholar 

  292. Reka, A. K. et al. Peroxisome proliferator-activated receptor-γ activation inhibits tumor metastasis by antagonizing Smad3-mediated epithelial–mesenchymal transition. Mol. Cancer Ther. 9, 3221–3232 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Liu, J. et al. Bergenin inhibits bladder cancer progression via activating the PPARγ/PTEN/Akt signal pathway. Drug Dev. Res. 82, 278–286 (2021).

    Article  CAS  PubMed  Google Scholar 

  294. Di Gregorio, J. et al. Role of glycogen synthase kinase-3β and PPAR-γ on epithelial-to-mesenchymal transition in DSS-induced colorectal fibrosis. PLoS ONE 12, e0171093 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  295. Wu, C. T., Wang, C. C., Huang, L. C., Liu, S. H. & Chiang, C. K. Plasticizer di-(2-ethylhexyl)phthalate induces epithelial-to-mesenchymal transition and renal fibrosis in vitro and in vivo. Toxicol. Sci. 164, 363–374 (2018).

    Article  CAS  PubMed  Google Scholar 

  296. Wang, Q. et al. Integrin β4 in EMT: an implication of renal diseases. Int. J. Clin. Exp. Med. 8, 6967–6976 (2015).

    PubMed  PubMed Central  Google Scholar 

  297. Bai, X., Hou, X., Tian, J., Geng, J. & Li, X. CDK5 promotes renal tubulointerstitial fibrosis in diabetic nephropathy via ERK1/2/PPARγ pathway. Oncotarget 7, 36510–36528 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  298. Li, R. et al. Curcumin inhibits transforming growth factor-β1-induced EMT via PPARγ pathway, not Smad pathway in renal tubular epithelial cells. PLoS ONE 8, e58848 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. Bocca, C. et al. Expression of Cox-2 in human breast cancer cells as a critical determinant of epithelial-to-mesenchymal transition and invasiveness. Expert. Opin. Ther. Targets 18, 121–135 (2014).

    Article  CAS  PubMed  Google Scholar 

  300. Li, Z. L. et al. COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells. Oncoimmunology 4, e1044712 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  302. Qin, G. et al. Palbociclib inhibits epithelial–mesenchymal transition and metastasis in breast cancer via c-Jun/COX-2 signaling pathway. Oncotarget 6, 41794–41808 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  303. Wang, Y. P., Wang, Q. Y., Li, C. H. & Li, X. W. COX-2 inhibition by celecoxib in epithelial ovarian cancer attenuates E-cadherin suppression through reduced Snail nuclear translocation. Chem. Biol. Interact. 292, 24–29 (2018).

    Article  CAS  PubMed  Google Scholar 

  304. Xu, Z. et al. Lipoxin A4 interferes with embryo implantation via suppression of epithelial–mesenchymal transition. Am. J. Reprod. Immunol. 81, e13107 (2019).

    Article  PubMed  Google Scholar 

  305. Wu, R. F. et al. Lipoxin A4 suppresses estrogen-induced epithelial–mesenchymal transition via ALXR-dependent manner in endometriosis. Reprod. Sci. 25, 566–578 (2018).

    Article  CAS  PubMed  Google Scholar 

  306. Yang, J. X. et al. Lipoxin A4 ameliorates lipopolysaccharide-induced lung injury through stimulating epithelial proliferation, reducing epithelial cell apoptosis and inhibits epithelial–mesenchymal transition. Respir. Res. 20, 192 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  307. Rodgers, K., McMahon, B., Mitchell, D., Sadlier, D. & Godson, C. Lipoxin A4 modifies platelet-derived growth factor-induced pro-fibrotic gene expression in human renal mesangial cells. Am. J. Pathol. 167, 683–694 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  308. Xu, F. et al. Lipoxin A4 and its analog suppress hepatocarcinoma cell epithelial–mesenchymal transition, migration and metastasis via regulating integrin-linked kinase axis. Prostaglandins Other Lipid Mediat. 137, 9–19 (2018).

    Article  CAS  PubMed  Google Scholar 

  309. Zong, L. et al. Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-β1 signaling in pancreatic cancer. J. Exp. Clin. Cancer Res. 36, 181 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  310. Warburg, O., Wind, F. & Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 8, 519–530 (1927).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  311. Hamabe, A. et al. Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial–mesenchymal transition. Proc. Natl Acad. Sci. USA 111, 15526–15531 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  312. Fan, F. T. et al. PKM2 regulates hepatocellular carcinoma cell epithelial–mesenchymal transition and migration upon EGFR activation. Asian Pac. J. Cancer Prev. 15, 1961–1970 (2014).

    Article  PubMed  Google Scholar 

  313. Chen, G. et al. Deregulation of hexokinase II is associated with glycolysis, autophagy, and the epithelial–mesenchymal transition in tongue squamous cell carcinoma under hypoxia. Biomed. Res. Int. 2018, 8480762 (2018).

    PubMed  PubMed Central  Google Scholar 

  314. Wang, Y. et al. LncRNA-p23154 promotes the invasion-metastasis potential of oral squamous cell carcinoma by regulating Glut1-mediated glycolysis. Cancer Lett. 434, 172–183 (2018).

    Article  CAS  PubMed  Google Scholar 

  315. Yalcin, A. et al. 6-Phosphofructo-2-kinase/fructose 2,6-bisphosphatase-3 is required for transforming growth factor β1-enhanced invasion of Panc1 cells in vitro. Biochem. Biophys. Res. Commun. 484, 687–693 (2017).

    Article  CAS  PubMed  Google Scholar 

  316. Lunetti, P. et al. Metabolic reprogramming in breast cancer results in distinct mitochondrial bioenergetics between luminal and basal subtypes. FEBS J. 286, 688–709 (2019).

    Article  CAS  PubMed  Google Scholar 

  317. Zhang, J. et al. TGF-β1 induces epithelial-to-mesenchymal transition via inhibiting mitochondrial functions in A549 cells. Free Radic. Res. 52, 1432–1444 (2018).

    Article  CAS  PubMed  Google Scholar 

  318. Yi, E. Y., Park, S. Y., Jung, S. Y., Jang, W. J. & Kim, Y. J. Mitochondrial dysfunction induces EMT through the TGF-β/Smad/Snail signaling pathway in Hep3B hepatocellular carcinoma cells. Int. J. Oncol. 47, 1845–1853 (2015).

    Article  CAS  PubMed  Google Scholar 

  319. Guha, M. et al. Mitochondrial retrograde signaling induces epithelial–mesenchymal transition and generates breast cancer stem cells. Oncogene 33, 5238–5250 (2014).

    Article  CAS  PubMed  Google Scholar 

  320. Li, X. et al. Upregulation of lactate-inducible snail protein suppresses oncogene-mediated senescence through p16INK4a inactivation. J. Exp. Clin. Cancer Res. 37, 39 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  321. Fiaschi, T. et al. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor–stroma interplay. Cancer Res. 72, 5130–5140 (2012).

    Article  CAS  PubMed  Google Scholar 

  322. Wang, H. et al. TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis. Endocr. Relat. Cancer 24, 565–578 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  323. Park, G. B. & Kim, D. TLR4-mediated galectin-1 production triggers epithelial–mesenchymal transition in colon cancer cells through ADAM10- and ADAM17-associated lactate production. Mol. Cell Biochem. 425, 191–202 (2017).

    Article  CAS  PubMed  Google Scholar 

  324. Corbet, C. et al. TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells. Nat. Commun. 11, 454 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  325. Bhattacharya, D., Azambuja, A. P. & Simoes-Costa, M. Metabolic reprogramming promotes neural crest migration via Yap/Tead signaling. Dev. Cell 53, 199–211.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  326. Bulusu, V. et al. Spatiotemporal analysis of a glycolytic activity gradient linked to mouse embryo mesoderm development. Dev. Cell 40, 331–341.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  327. Oginuma, M. et al. A gradient of glycolytic activity coordinates FGF and Wnt signaling during elongation of the body axis in amniote embryos. Dev. Cell 40, 342–353.e10 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  328. Youssef, K. K. & Nieto, M. A. Glucose metabolism takes center stage in epithelial–mesenchymal plasticity. Dev. Cell 53, 133–135 (2020).

    Article  CAS  PubMed  Google Scholar 

  329. Rossi, M. et al. PHGDH heterogeneity potentiates cancer cell dissemination and metastasis. Nature 605, 747–753 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  330. Schwager, S. C. et al. Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity. iScience 25, 105190 (2022). This report links migratory ability and EMT status to glucose metabolism in triple-negative breast cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  331. Siddiqui, A. et al. Thymidylate synthase maintains the de-differentiated state of triple negative breast cancers. Cell Death Differ. 26, 2223–2236 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  332. Ramesh, V., Brabletz, T. & Ceppi, P. Targeting EMT in cancer with repurposed metabolic inhibitors. Trends Cancer 6, 942–950 (2020).

    Article  CAS  PubMed  Google Scholar 

  333. Luond, F. et al. Distinct contributions of partial and full EMT to breast cancer malignancy. Dev. Cell 56, 3203–3221 e3211 (2021). Using tracing systems, this study finds that partial, but not full, EMT contributes to metastasis, whereas full EMT contributes to chemoresistance.

    Article  CAS  PubMed  Google Scholar 

  334. Verstappe, J. & Berx, G. A role for partial epithelial-to-mesenchymal transition in enabling stemness in homeostasis and cancer. Semin. Cancer Biol. 90, 15–28 (2023).

    Article  CAS  PubMed  Google Scholar 

  335. Lambert, A. W. & Weinberg, R. A. Linking EMT programmes to normal and neoplastic epithelial stem cells. Nat. Rev. Cancer 21, 325–338 (2021).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  337. Schliekelman, M. J. et al. Molecular portraits of epithelial, mesenchymal, and hybrid states in lung adenocarcinoma and their relevance to survival. Cancer Res. 75, 1789–1800 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  338. Ruscetti, M., Quach, B., Dadashian, E. L., Mulholland, D. J. & Wu, H. Tracking and functional characterization of epithelial–mesenchymal transition and mesenchymal tumor cells during prostate cancer metastasis. Cancer Res. 75, 2749–2759 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  339. Cook, D. P. & Wrana, J. L. A specialist-generalist framework for epithelial–mesenchymal plasticity in cancer. Trends Cancer 8, 358–368 (2022).

    Article  CAS  PubMed  Google Scholar 

  340. Saxena, K., Jolly, M. K. & Balamurugan, K. Hypoxia, partial EMT and collective migration: emerging culprits in metastasis. Transl. Oncol. 13, 100845 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  341. Quan, Q. et al. Cancer stem-like cells with hybrid epithelial/mesenchymal phenotype leading the collective invasion. Cancer Sci. 111, 467–476 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  342. Jia, D. et al. OVOL guides the epithelial–hybrid–mesenchymal transition. Oncotarget 6, 15436–15448 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  343. Jolly, M. K. et al. Stability of the hybrid epithelial/mesenchymal phenotype. Oncotarget 7, 27067–27084 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  344. Bocci, F. et al. Numb prevents a complete epithelial–mesenchymal transition by modulating Notch signalling. J. R. Soc. Interface https://doi.org/10.1098/rsif.2017.0512 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  345. Subbalakshmi, A. R. et al. NFATc acts as a non-canonical phenotypic stability factor for a hybrid epithelial/mesenchymal phenotype. Front. Oncol. 10, 553342 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  346. Vilchez Mercedes, S. A. et al. Nrf2 modulates the hybrid epithelial/mesenchymal phenotype and notch signaling during collective cancer migration. Front. Mol. Biosci. 9, 807324 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  347. Bocci, F. et al. NRF2 activates a partial epithelial–mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype. Integr. Biol. 11, 251–263 (2019).

    Article  Google Scholar 

  348. Chung, V. Y. et al. GRHL2–miR-200–ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification. Sci. Rep. 6, 19943 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  349. Jolly, M. K. et al. Inflammatory breast cancer: a model for investigating cluster-based dissemination. NPJ Breast Cancer 3, 21 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  350. Subbalakshmi, A. R., Sahoo, S., Biswas, K. & Jolly, M. K. A computational systems biology approach identifies SLUG as a mediator of partial epithelial–mesenchymal transition (EMT). Cells Tissues Organs 211, 689–702 (2021).

    Article  PubMed  Google Scholar 

  351. Biswas, K., Jolly, M. K. & Ghosh, A. Stability and mean residence times for hybrid epithelial/mesenchymal phenotype. Phys. Biol. 16, 025003 (2019).

    Article  CAS  PubMed  Google Scholar 

  352. Zander, M. A., Cancino, G. I., Gridley, T., Kaplan, D. R. & Miller, F. D. The Snail transcription factor regulates the numbers of neural precursor cells and newborn neurons throughout mammalian life. PLoS ONE 9, e104767 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  353. Wang, H. et al. ZEB1 represses neural differentiation and cooperates with CTBP2 to dynamically regulate cell migration during neocortex development. Cell Rep. 27, 2335–2353.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  354. Deryckere, A. et al. Multifaceted actions of Zeb2 in postnatal neurogenesis from the ventricular–subventricular zone to the olfactory bulb. Development https://doi.org/10.1242/dev.184861 (2020).

    Article  PubMed  Google Scholar 

  355. Di Filippo, E. S. et al. Zeb2 Regulates myogenic differentiation in pluripotent stem cells. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21072525 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  356. Choi, I. Y. et al. Transcriptional landscape of myogenesis from human pluripotent stem cells reveals a key role of TWIST1 in maintenance of skeletal muscle progenitors. eLife https://doi.org/10.7554/eLife.46981 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  357. Gubelmann, C. et al. Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network. eLife 3, e03346 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  358. Goossens, S. et al. The EMT regulator Zeb2/Sip1 is essential for murine embryonic hematopoietic stem/progenitor cell differentiation and mobilization. Blood 117, 5620–5630 (2011).

    Article  CAS  PubMed  Google Scholar 

  359. Scott, C. L. & Omilusik, K. D. ZEBs: novel players in immune cell development and function. Trends Immunol. 40, 431–446 (2019).

    Article  CAS  PubMed  Google Scholar 

  360. Wang, J. et al. Interplay between the EMT transcription factors ZEB1 and ZEB2 regulates hematopoietic stem and progenitor cell differentiation and hematopoietic lineage fidelity. PLoS Biol. 19, e3001394 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  361. Denecker, G. et al. Identification of a ZEB2–MITF–ZEB1 transcriptional network that controls melanogenesis and melanoma progression. Cell Death Differ. 21, 1250–1261 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  362. Bruneel, K., Verstappe, J., Vandamme, N. & Berx, G. Intrinsic balance between ZEB family members is important for melanocyte homeostasis and melanoma progression. Cancers https://doi.org/10.3390/cancers12082248 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  363. Vandamme, N. & Berx, G. Melanoma cells revive an embryonic transcriptional network to dictate phenotypic heterogeneity. Front. Oncol. 4, 352 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  364. Goossens, S. et al. ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling. Nat. Commun. 6, 5794 (2015).

    Article  CAS  PubMed  Google Scholar 

  365. Tang, Y., Durand, S., Dalle, S. & Caramel, J. EMT-inducing transcription factors, drivers of melanoma phenotype switching, and resistance to treatment. Cancers https://doi.org/10.3390/cancers12082154 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  366. Pedri, D., Karras, P., Landeloos, E., Marine, J. C. & Rambow, F. Epithelial-to-mesenchymal-like transition events in melanoma. FEBS J. 289, 1352–1368 (2022).

    Article  CAS  PubMed  Google Scholar 

  367. Soen, B. et al. ZEB proteins in leukemia: friends, foes, or friendly foes. Hemasphere 2, e43 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  368. Goossens, S. et al. ZEB2 and LMO2 drive immature T-cell lymphoblastic leukemia via distinct oncogenic mechanisms. Haematologica 104, 1608–1616 (2019).

    Article  CAS  PubMed