Epithelial-to-mesenchymal transition in cancer: complexity and opportunities

Abstract

The cell-biological program termed the epithelial-to-mesenchymal transition (EMT) plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenchymal phenotypic axis. These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse. Currently we still lack a coherent overview of the molecular and biochemical mechanisms inducing cells to enter various states along the epithelial-mesenchymal phenotypic spectrum. An improved understanding of the dynamic and plastic nature of the EMT program has the potential to yield novel therapies targeting this cellular program that may aid in the management of high-grade malignancies.

References 112

1. 1.

   Nieto MA, Huang RYJ, Jackson RA, Thiery JP. EMT: 2016. Cell 2016; 166(1): 21–45

   Not in our library10.1016/j.cell.2016.06.028

2. 2.

   Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009; 9(4): 265–273

   Not in our library10.1038/nrc2620

3. 3.

   Greenburg G, Hay ED. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol 1982; 95(1): 333–339

   Not in our library10.1083/jcb.95.1.333

4. 4.

   Lim J, Thiery JP. Epithelial-mesenchymal transitions: insights from development. Development 2012; 139(19): 3471–3486

   Not in our library10.1242/dev.071209

5. 5.

   Carver EA, Jiang R, Lan Y, Oram KF, Gridley T. The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol Cell Biol 2001; 21(23): 8184–8188

   Not in our library10.1128/mcb.21.23.8184-8188.2001

6. 6.

   Chen ZF, Behringer RR. twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev 1995; 9(6): 686–699

   Not in our library10.1101/gad.9.6.686

7. 7.

   Van de Putte T, Maruhashi M, Francis A, Nelles L, Kondoh H, Huylebroeck D, Higashi Y. 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 2003; 72(2): 465–470

   Not in our library10.1086/346092

8. 8.

   Jiang R, Lan Y, Norton CR, Sundberg JP, Gridley T. The Slug gene is not essential for mesoderm or neural crest development in mice. Dev Biol 1998; 198(2): 277–285

   Not in our library

9. 9.

   Higashi Y, Moribe H, Takagi T, Sekido R, Kawakami K, Kikutani H, Kondoh H. Impairment of T cell development in δEF1 mutant mice. J Exp Med 1997; 185(8): 1467–1479

   Not in our library10.1084/jem.185.8.1467

10. 10.

    Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 2017; 14(10): 611–629

    Not in our library10.1038/nrclinonc.2017.44

11. 11.

    Shaw TJ, Martin P. Wound repair: a showcase for cell plasticity and migration. Curr Opin Cell Biol 2016; 42: 29–37

    Not in our library10.1016/j.ceb.2016.04.001

12. 12.

    Ye X, Weinberg RA. Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol 2015; 25(11): 675–686

    Not in our library10.1016/j.tcb.2015.07.012

13. 13.

    Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell 2017; 168(4): 670–691

    Not in our library10.1016/j.cell.2016.11.037

14. 14.

    Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2(6): 442–454

    Not in our library10.1038/nrc822

15. 15.

    Thompson L, Chang B, Barsky SH. Monoclonal origins of malignant mixed tumors (carcinosarcomas). Evidence for a divergent histogenesis. Am J Surg Pathol 1996; 20(3): 277–285

    Not in our library10.1097/00000478-199603000-00003

16. 16.

    Tsai JH, Yang J. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev 2013; 27(20): 2192–2206

    Not in our library10.1101/gad.225334.113

17. 17.

    Ocaña OH, Córcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S, Barrallo-Gimeno A, Cano A, Nieto MA. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 2012; 22(6): 709–724

    Not in our library10.1016/j.ccr.2012.10.012

18. 18.

    Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 2012; 22(6): 725–736

    Not in our library10.1016/j.ccr.2012.09.022

19. 19.

    Lawson DA, Bhakta NR, Kessenbrock K, Prummel KD, Yu Y, Takai K, Zhou A, Eyob H, Balakrishnan S, Wang CY, Yaswen P, Goga A, Werb Z. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature 2015; 526(7571): 131–135

    Not in our library10.1038/nature15260

20. 20.

    Pattabiraman DR, Weinberg RA. Tackling the cancer stem cells—what challenges do they pose? Nat Rev Drug Discov 2014; 13(7): 497–512

    Not in our library10.1038/nrd4253

21. 21.

    Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells — an integrated concept of malignant tumour progression. Nat Rev Cancer 2005; 5(9): 744–749

    Not in our library10.1038/nrc1694

22. 22.

    Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelialmesenchymal transition generates cells with properties of stem cells. Cell 2008; 133(4): 704–715

    Not in our library10.1016/j.cell.2008.03.027

23. 23.

    Guo W, Keckesova Z, Donaher JL, Shibue T, Tischler V, Reinhardt F, Itzkovitz S, Noske A, Zürrer-Härdi U, Bell G, Tam WL, Mani SA, van Oudenaarden A, Weinberg RA. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 2012; 148(5): 1015–1028

    Not in our library10.1016/j.cell.2012.02.008

24. 24.
    Generation of Breast Cancer Stem Cells through Epithelial-Mesenchymal Transition · 2008

    No notice
25. 25.

    Rasheed ZA, Yang J, Wang Q, Kowalski J, Freed I, Murter C, Hong SM, Koorstra JB, Rajeshkumar NV, He X, Goggins M, Iacobuzio-Donahue C, Berman DM, Laheru D, Jimeno A, Hidalgo M, Maitra A, Matsui W. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst 2010; 102(5): 340–351

    Not in our library10.1093/jnci/djp535

26. 26.
    Epithelial to Mesenchymal Transition Is Mechanistically Linked with Stem Cell Signatures in Prostate Cancer Cells · 2010

    No notice
27. 27.
    Overexpression of Snail induces epithelial–mesenchymal transition and a cancer stem cell–like phenotype in human colorectal cancer cells · 2012

    No notice
28. 28.

    Long H, Xiang T, Qi W, Huang J, Chen J, He L, Liang Z, Guo B, Li Y, Xie R, Zhu B. CD133+ ovarian cancer stem-like cells promote non-stem cancer cell metastasis via CCL5 induced epithelial-mesenchymal transition. Oncotarget 2015; 6(8): 5846–5859

    Not in our library10.18632/oncotarget.3462

29. 29.

    Ye X, Tam WL, Shibue T, Kaygusuz Y, Reinhardt F, Ng Eaton E, Weinberg RA. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 2015; 525(7568): 256–260

    Not in our library10.1038/nature14897

30. 30.

    Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, Brooks M, Reinhardt F, Su Y, Polyak K, Arendt LM, Kuperwasser C, Bierie B, Weinberg RA. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A 2011; 108(19): 7950–7955

    Not in our library10.1073/pnas.1102454108

31. 31.

    Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, D’Alessio AC, Young RA, Weinberg RA. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 2013; 154(1): 61–74

    Not in our library10.1016/j.cell.2013.06.005

32. 32.

    Del Pozo Martin Y, Park D, Ramachandran A, Ombrato L, Calvo F, Chakravarty P, Spencer-Dene B, Derzsi S, Hill CS, Sahai E, Malanchi I. Mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization. Cell Rep 2015; 13(11): 2456–2469

    Not in our library10.1016/j.celrep.2015.11.025

33. 33.

    Bierie B, Pierce SE, Kroeger C, Stover DG, Pattabiraman DR, Thiru P, Liu Donaher J, Reinhardt F, Chaffer CL, Keckesova Z, Weinberg RA. Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells. Proc Natl Acad Sci U S A 2017; 114(12): E2337–E2346

    Not in our library10.1073/pnas.1618298114

34. 34.

    Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer 2006; 6(6): 449–458

    Not in our library10.1038/nrc1886

35. 35.

    Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004; 117(7): 927–939

    Not in our library10.1016/j.cell.2004.06.006

36. 36.

    Krebs AM, Mitschke J, Lasierra Losada M, Schmalhofer O, Boerries M, Busch H, Boettcher M, Mougiakakos D, Reichardt W, Bronsert P, Brunton VG, Pilarsky C, Winkler TH, Brabletz S, Stemmler MP, Brabletz T. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol 2017; 19(5): 518–529

    Not in our library10.1038/ncb3513

37. 37.

    Friedl P, Locker J, Sahai E, Segall JE. Classifying collective cancer cell invasion. Nat Cell Biol 2012; 14(8): 777–783

    Not in our library10.1038/ncb2548

38. 38.

    Friedl P, Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 2009; 10(7): 445–457

    Not in our library10.1038/nrm2720

39. 39.

    Cheung KJ, Padmanaban V, Silvestri V, Schipper K, Cohen JD, Fairchild AN, Gorin MA, Verdone JE, Pienta KJ, Bader JS, Ewald AJ. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc Natl Acad Sci U S A 2016; 113(7): E854–E863

    Not in our library10.1073/pnas.1508541113

40. 40.

    Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Brannigan BW, Kapur R, Stott SL, Shioda T, Ramaswamy S, Ting DT, Lin CP, Toner M, Haber DA, Maheswaran S. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 2014; 158(5): 1110–1122

    Not in our library10.1016/j.cell.2014.07.013

41. 41.

    Revenu C, Gilmour D. EMT 2.0: shaping epithelia through collective migration. Curr Opin Genet Dev 2009; 19(4): 338–342

    Not in our library10.1016/j.gde.2009.04.007

42. 42.

    Westcott JM, Prechtl AM, Maine EA, Dang TT, Esparza MA, Sun H, Zhou Y, Xie Y, Pearson GW. An epigenetically distinct breast cancer cell subpopulation promotes collective invasion. J Clin Invest 2015; 125(5): 1927–1943

    Not in our library10.1172/jci77767

43. 43.

    Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, Rodman C, Luo CL, Mroz EA, Emerick KS, Deschler DG, Varvares MA, Mylvaganam R, Rozenblatt-Rosen O, Rocco JW, Faquin WC, Lin DT, Regev A, Bernstein BE. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 2017; 171(7): 1611–1624. e24

    Not in our library10.1016/j.cell.2017.10.044

44. 44.

    Kourtidis A, Ngok SP, Pulimeno P, Feathers RW, Carpio LR, Baker TR, Carr JM, Yan IK, Borges S, Perez EA, Storz P, Copland JA, Patel T, Thompson EA, Citi S, Anastasiadis PZ. Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity. Nat Cell Biol 2015; 17(9): 1145–1157

    Not in our library10.1038/ncb3227

45. 45.

    Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, Concannon KF, Donaldson MC, Sequist LV, Brachtel E, Sgroi D, Baselga J, Ramaswamy S, Toner M, Haber DA, Maheswaran S. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 2013; 339(6119): 580–584

    Not in our library10.1126/science.1228522

46. 46.

    Naumov GN, MacDonald IC, Weinmeister PM, Kerkvliet N, Nadkarni KV, Wilson SM, Morris VL, Groom AC, Chambers AF. Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res 2002; 62(7): 2162–2168

    Not in our library

47. 47.

    Heiss MM, Allgayer H, Gruetzner KU, Funke I, Babic R, Jauch KW, Schildberg FW. Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer. Nat Med 1995; 1(10): 1035–1039

    Not in our library10.1038/nm1095-1035

48. 48.

    Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D, Haley B, Morrison L, Fleming TP, Herlyn D, Terstappen LWMM, Fehm T, Tucker TF, Lane N, Wang J, Uhr JW. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 2004; 10(24): 8152–8162

    Not in our library10.1158/1078-0432.ccr-04-1110

49. 49.

    Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 2007; 7(11): 834–846

    Not in our library10.1038/nrc2256

50. 50.

    Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GYC, Bliss J, Vincent-Salomon A, Pantel K. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 2005; 353(8): 793–802

    Not in our library10.1056/nejmoa050434

51. 51.

    Hüsemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmüller G, Klein CA. Systemic spread is an early step in breast cancer. Cancer Cell 2008; 13(1): 58–68

    Not in our library10.1016/j.ccr.2007.12.003

52. 52.

    Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ. EMT and dissemination precede pancreatic tumor formation. Cell 2012; 148(1–2): 349–361

    Not in our library10.1016/j.cell.2011.11.025

53. 53.

    Klein CA. Selection and adaptation during metastatic cancer progression. Nature 2013; 501(7467): 365–372

    Not in our library10.1038/nature12628

54. 54.

    Takano S, Reichert M, Bakir B, Das KK, Nishida T, Miyazaki M, Heeg S, Collins MA, Marchand B, Hicks PD, Maitra A, Rustgi AK. Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization. Genes Dev 2016; 30(2): 233–247

    Not in our library10.1101/gad.263327.115

55. 55.

    Berx G, Cleton-Jansen AM, Strumane K, de Leeuw WJ, Nollet F, van Roy F, Cornelisse C. E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 1996; 13(9): 1919–1925

    Not in our library

56. 56.

    Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366(10): 883–892

    Not in our library10.1056/nejmoa1113205

57. 57.

    Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 2009; 138(5): 822–829

    Not in our library10.1016/j.cell.2009.08.017

58. 58.

    Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013; 501(7467): 328–337

    Not in our library10.1038/nature12624

59. 59.

    Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol 2018; 15(2): 81–94

    Not in our library10.1038/nrclinonc.2017.166

60. 60.

    Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature 2013; 501(7467): 338–345

    Not in our library10.1038/nature12625

61. 61.

    Koren S, Reavie L, Couto JP, De Silva D, Stadler MB, Roloff T, Britschgi A, Eichlisberger T, Kohler H, Aina O, Cardiff RD, Bentires-Alj M. PIK3CA(H1047R) induces multipotency and multi-lineage mammary tumours. Nature 2015; 525(7567): 114–118

    Not in our library10.1038/nature14669

62. 62.

    Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, Wongvipat J, Ku SY, Gao D, Cao Z, Shah N, Adams EJ, Abida W, Watson PA, Prandi D, Huang CH, de Stanchina E, Lowe SW, Ellis L, Beltran H, Rubin MA, Goodrich DW, Demichelis F, Sawyers CL. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 2017; 355 (6320): 84–88

    Not in our library10.1126/science.aah4307

63. 63.

    Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, Goodrich MM, Labbé DP, Gomez EC, Wang J, Long HW, Xu B, Brown M, Loda M, Sawyers CL, Ellis L, Goodrich DW. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 2017; 355(6320): 78–83

    Not in our library10.1126/science.aah4199

64. 64.

    Pastushenko I, Brisebarre A, Sifrim A, Fioramonti M, Revenco T, Boumahdi S, Van Keymeulen A, Brown D, Moers V, Lemaire S, De Clercq S, Minguijón E, Balsat C, Sokolow Y, Dubois C, De Cock F, Scozzaro S, Sopena F, Lanas A, D’Haene N, Salmon I, Marine JC, Voet T, Sotiropoulou PA, Blanpain C. Identification of the tumour transition states occurring during EMT. Nature 2018; 556(7702): 463–468

    Not in our library10.1038/s41586-018-0040-3

65. 65.

    Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelialmesenchymal transitions in development and disease. Cell 2009; 139(5): 871–890

    Not in our library10.1016/j.cell.2009.11.007

66. 66.

    Dembinski JL, Krauss S. Characterization and functional analysis of a slow cycling stem cell-like subpopulation in pancreas adenocarcinoma. Clin Exp Metastasis 2009; 26(7): 611–623

    Not in our library10.1007/s10585-009-9260-0

67. 67.

    Vega S, Morales AV, Ocaña OH, Valdés F, Fabregat I, Nieto MA. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 2004; 18(10): 1131–1143

    Not in our library10.1101/gad.294104

68. 68.

    Saxena M, Stephens MA, Pathak H, Rangarajan A. Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death Dis 2011; 2(7): e179–e179

    Not in our library10.1038/cddis.2011.61

69. 69.

    Gjerdrum C, Tiron C, Høiby T, Stefansson I, Haugen H, Sandal T, Collett K, Li S, McCormack E, Gjertsen BT, Micklem DR, Akslen LA, Glackin C, Lorens JB. Axl is an essential epithelial-tomesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci U S A 2010; 107(3): 1124–1129

    Not in our library10.1073/pnas.0909333107

70. 70.

    Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, Shen L, Fan Y, Giri U, Tumula PK, Nilsson MB, Gudikote J, Tran H, Cardnell RJG, Bearss DJ, Warner SL, Foulks JM, Kanner SB, Gandhi V, Krett N, Rosen ST, Kim ES, Herbst RS, Blumenschein GR, Lee JJ, Lippman SM, Ang KK, Mills GB, Hong WK, Weinstein JN, Wistuba II, Coombes KR, Minna JD, Heymach JV. 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 2013; 19(1): 279–290

    Not in our library10.1158/1078-0432.ccr-12-1558

71. 71.

    Hata AN, Niederst MJ, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Mulvey HE, Maruvka YE, Ji F, Bhang HEC, Krishnamurthy Radhakrishna V, Siravegna G, Hu H, Raoof S, Lockerman E, Kalsy A, Lee D, Keating CL, Ruddy DA, Damon LJ, Crystal AS, Costa C, Piotrowska Z, Bardelli A, Iafrate AJ, Sadreyev RI, Stegmeier F, Getz G, Sequist LV, Faber AC, Engelman JA. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med 2016; 22(3): 262–269

    Not in our library10.1038/nm.4040

72. 72.

    Bhang HEC, Ruddy DA, Krishnamurthy Radhakrishna V, Caushi JX, Zhao R, Hims MM, Singh AP, Kao I, Rakiec D, Shaw P, Balak M, Raza A, Ackley E, Keen N, Schlabach MR, Palmer M, Leary RJ, Chiang DY, Sellers WR, Michor F, Cooke VG, Korn JM, Stegmeier F. Studying clonal dynamics in response to cancer therapy using high-complexity barcoding. Nat Med 2015; 21(5): 440–448

    Not in our library10.1038/nm.3841

73. 73.
    New insights into the role of EMT in tumor immune escape · 2017

    No notice
74. 74.

    Hamilton DH, Huang B, Fernando RI, Tsang KY, Palena C. WEE1 inhibition alleviates resistance to immune attack of tumor cells undergoing epithelial-mesenchymal transition. Cancer Res 2014; 74(9): 2510–2519

    Not in our library10.1158/0008-5472.can-13-1894

75. 75.

    Akalay I, Janji B, Hasmim M, Noman MZ, André F, De Cremoux P, Bertheau P, Badoual C, Vielh P, Larsen AK, Sabbah M, Tan TZ, Keira JH, Hung NTY, Thiery JP, Mami-Chouaib F, Chouaib S. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis. Cancer Res 2013; 73(8): 2418–2427

    Not in our library10.1158/0008-5472.can-12-2432

76. 76.

    Dongre A, Rashidian M, Reinhardt F, Bagnato A, Keckesova Z, Ploegh HL, Weinberg RA. Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res 2017; 77(15): 3982–3989

    Not in our library10.1158/0008-5472.can-16-3292

77. 77.

    Chen L, Gibbons DL, Goswami S, Cortez MA, Ahn YH, Byers LA, Zhang X, Yi X, Dwyer D, Lin W, Diao L, Wang J, Roybal J, Patel M, Ungewiss C, Peng D, Antonia S, Mediavilla-Varela M, Robertson G, Suraokar M, Welsh JW, Erez B, Wistuba II, Chen L, Peng D, Wang S, Ullrich SE, Heymach JV, Kurie JM, Qin FXF. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun 2014; 5(1): 5241

    Not in our library10.1038/ncomms6241

78. 78.

    Noman MZ, Janji B, Abdou A, Hasmim M, Terry S, Tan TZ, Mami-Chouaib F, Thiery JP, Chouaib S. The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200. Oncoimmunology 2017; 6(1): e1263412

    Not in our library10.1080/2162402x.2016.1263412

79. 79.

    Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 2009; 15(3): 195–206

    Not in our library10.1016/j.ccr.2009.01.023

80. 80.

    Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 2007; 7(6): 415–428

    Not in our library10.1038/nrc2131

81. 81.

    Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15(3): 178–196

    Not in our library10.1038/nrm3758

82. 82.

    Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu CC, LeBleu VS, Kalluri R. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015; 527(7579): 525–530

    Not in our library10.1038/nature16064

83. 83.

    Aiello NM, Brabletz T, Kang Y, Nieto MA, Weinberg RA, Stanger BZ. Upholding a role for EMT in pancreatic cancer metastasis. Nature 2017; 547(7661): E7–E8

    Not in our library10.1038/nature22963

84. 84.

    Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013; 19(11): 1423–1437

    Not in our library10.1038/nm.3394

85. 85.

    Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 2008; 10(5): 593–601

    Not in our library10.1038/ncb1722

86. 86.

    Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 2008; 22(7): 894–907

    Not in our library10.1101/gad.1640608

87. 87.

    Korpal M, Lee ES, Hu G, Kang Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 2008; 283(22): 14910–14914

    Not in our library10.1074/jbc.c800074200

88. 88.

    Siemens H, Jackstadt R, Hünten S, Kaller M, Menssen A, Götz U, Hermeking H. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle 2011; 10(24): 4256–4271

    Not in our library10.4161/cc.10.24.18552

89. 89.

    Chakrabarti R, Hwang J, Andres Blanco M, Wei Y, Lukačišin M, Romano RA, Smalley K, Liu S, Yang Q, Ibrahim T, Mercatali L, Amadori D, Haffty BG, Sinha S, Kang Y. Elf5 inhibits the epithelial-mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2. Nat Cell Biol 2012; 14(11): 1212–1222

    Not in our library10.1038/ncb2607

90. 90.

    Cieply B, Riley P 4th, Pifer PM, Widmeyer J, Addison JB, Ivanov AV, Denvir J, Frisch SM. Suppression of the epithelialmesenchymal transition by Grainyhead-like-2. Cancer Res 2012; 72(9): 2440–2453

    Not in our library10.1158/0008-5472.can-11-4038

91. 91.

    Watanabe K, Villarreal-Ponce A, Sun P, Salmans ML, Fallahi M, Andersen B, Dai X. Mammary morphogenesis and regeneration require the inhibition of EMT at terminal end buds by Ovol2 transcriptional repressor. Dev Cell 2014; 29(1): 59–74

    Not in our library10.1016/j.devcel.2014.03.006

92. 92.

    Chang CJ, Chao CH, Xia W, Yang JY, Xiong Y, Li CW, Yu WH, Rehman SK, Hsu JL, Lee HH, Liu M, Chen CT, Yu D, Hung MC. p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol 2011; 13(3): 317–323

    Not in our library10.1038/ncb2173

93. 93.
    An EMT–Driven Alternative Splicing Program Occurs in Human Breast Cancer and Modulates Cellular Phenotype · 2011

    No notice
94. 94.

    Warzecha CC, Sato TK, Nabet B, Hogenesch JB, Carstens RP. ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Mol Cell 2009; 33(5): 591–601

    Not in our library10.1016/j.molcel.2009.01.025

95. 95.

    Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, Roslan S, Schreiber AW, Gregory PA, Goodall GJ. The RNA binding protein quaking regulates formation of circRNAs. Cell 2015; 160(6): 1125–1134

    Not in our library10.1016/j.cell.2015.02.014

96. 96.

    Braeutigam C, Rago L, Rolke A, Waldmeier L, Christofori G, Winter J. The RNA-binding protein Rbfox2: an essential regulator of EMT-driven alternative splicing and a mediator of cellular invasion. Oncogene 2014; 33(9): 1082–1092

    Not in our library10.1038/onc.2013.50

97. 97.

    Peinado H, Ballestar E, Esteller M, Cano A. Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol 2004; 24(1): 306–319

    Not in our library10.1128/mcb.24.1.306-319.2004

98. 98.

    Lin Y, Wu Y, Li J, Dong C, Ye X, Chi YI, Evers BM, Zhou BP. The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J 2010; 29(11): 1803–1816

    Not in our library10.1038/emboj.2010.63

99. 99.

    Herranz N, Pasini D, Díaz VM, Francí C, Gutierrez A, Dave N, Escrivà M, Hernandez-Muñoz I, Di Croce L, Helin K, García de Herreros A, Peiró S. Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol Cell Biol 2008; 28(15): 4772–4781

    Not in our library10.1128/mcb.00323-08

100. 100.

     Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC. Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004; 6(10): 931–940

     Not in our library10.1038/ncb1173

101. 101.

     Hong J, Zhou J, Fu J, He T, Qin J, Wang L, Liao L, Xu J. Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. Cancer Res 2011; 71(11): 3980–3990

     Not in our library10.1158/0008-5472.can-10-2914

102. 102.

     Xu J, Lamouille S, Derynck R. TGF-β-induced epithelial to mesenchymal transition. Cell Res 2009; 19(2): 156–172

     Not in our library10.1038/cr.2009.5

103. 103.

     Brown KA, Aakre ME, Gorska AE, Price JO, Eltom SE, Pietenpol JA, Moses HL. Induction by transforming growth factor-β1 of epithelial to mesenchymal transition is a rare event in vitro. Breast Cancer Res 2004; 6(3): R215–R231

     Not in our library10.1186/bcr778

104. 104.

     Lu H, Clauser KR, Tam WL, Fröse J, Ye X, Eaton EN, Reinhardt F, Donnenberg VS, Bhargava R, Carr SA, Weinberg RA. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol 2014; 16(11): 1105–1117

     Not in our library10.1038/ncb3041

105. 105.

     Li HJ, Reinhardt F, Herschman HR, Weinberg RA. Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling. Cancer Discov 2012; 2(9): 840–855

     Not in our library10.1158/2159-8290.cd-12-0101

106. 106.

     Byers L, Gerber D, Peguero J, Micklem D, Yule M, Lorens JB. 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 2016; 69: S18–S19

     Not in our library

107. 107.

     Sheridan C First Axl inhibitor enters clinical trials. Nat Biotechnol 2013; 31(9): 775–776

     Not in our library10.1038/nbt0913-775a

108. 108.

     Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, Galeas J, Dhruv HD, Berens ME, Schreiber SL, McCormick F, McManus MT. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 2017; 551(7679): 247–250

     Not in our library10.1038/nature24297

109. 109.

     Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, Kaffenberger SD, Eaton JK, Shimada K, Aguirre AJ, Viswanathan SR, Chattopadhyay S, Tamayo P, Yang WS, Rees MG, Chen S, Boskovic ZV, Javaid S, Huang C, Wu X, Tseng YY, Roider EM, Gao D, Cleary JM, Wolpin BM, Mesirov JP, Haber DA, Engelman JA, Boehm JS, Kotz JD, Hon CS, Chen Y, Hahn WC, Levesque MP, Doench JG, Berens ME, Shamji AF, Clemons PA, Stockwell BR, Schreiber SL. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 2017; 547(7664): 453–457

     Not in our library10.1038/nature23007

110. 110.

     Pattabiraman DR, Bierie B, Kober KI, Thiru P, Krall JA, Zill C, Reinhardt F, Tam WL, Weinberg RA. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. Science 2016; 351(6277): aad3680

     Not in our library10.1126/science.aad3680

111. 111.

     Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, Estrem ST, Cleverly AL, Desaiah D, Guba SC, Benhadji KA, Slapak CA, Lahn MM. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-β signaling pathway. Drug Des Devel Ther 2015; 9: 4479–4499

     Not in our library10.2147/dddt.s86621

112. 112.

     Liu X, Sun H, Qi J, Wang L, He S, Liu J, Feng C, Chen C, Li W, Guo Y, Qin D, Pan G, Chen J, Pei D, Zheng H. Sequential introduction of reprogramming factors reveals a time-sensitive requirement for individual factors and a sequential EMT-MET mechanism for optimal reprogramming. Nat Cell Biol 2013; 15(7): 829–838

     Not in our library10.1038/ncb2765

Cited by papers we hold 7

• Gut modulation to regulate NF-κB in colorectal and gastric cancer therapy and inflammation · 2025
  Not checked
• TGF-β signaling: critical nexus of fibrogenesis and cancer · 2024
  No notice
• ENO1 and Cancer · 2022
  No notice
• The many faces of cancer evolution · 2021
  Not checked
• Interrogation of the microenvironmental landscape in spinal ependymomas reveals dual functions of tumor-associated macrophages · 2021
  Not checked
• BTG1 inhibits malignancy as a novel prognosis signature in endometrial carcinoma · 2020
  Not checked
• Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis · 2018
  No notice

Reads

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