Implications of the hybrid epithelial/mesenchymal phenotype in metastasis

Frontiers in Oncology

Volumn 5, Issue JUN, 2015, Pages

  Jolly, Mohit Kumar ^a,b   Boareto, Marcelo ^a,d   Huang, Bin ^a   Jia, Dongya ^a,c   Lu, Mingyang ^a   Onuchic, Jose' N ^a   Levine, Herbert ^a,b   Ben Jacob, Eshel ^a,d  

^a RICE UNIVERSITY   (United States)

^b Rice University   (United States)

^c TEL AVIV UNIVERSITY   (Israel)

^d UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

Cancer stem cells; Cancer systems biology; Cell fate decisions; Intermediate EMT; Partial EMT

Indexed keywords

CD24 ANTIGEN; EPIDERMAL GROWTH FACTOR; EPITHELIAL CELL ADHESION MOLECULE; FIBROBLAST GROWTH FACTOR; GAMMA INTERFERON; HERMES ANTIGEN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 6; JAGGED1; MICRORNA 200; NOTCH RECEPTOR; OCTAMER TRANSCRIPTION FACTOR 4; PROTEIN P53; RAC1 PROTEIN; SCATTER FACTOR; SOMATOMEDIN BINDING PROTEIN; TRANSCRIPTION FACTOR CDX2; TRANSCRIPTION FACTOR SNAIL; TRANSCRIPTION FACTOR TWIST; TRANSCRIPTION FACTOR ZEB1; TRANSFORMING GROWTH FACTOR BETA; WNT PROTEIN;

ACTIN POLYMERIZATION; ARTICLE; CANCER CHEMOTHERAPY; CANCER RADIOTHERAPY; CARCINOMA; CASTRATION RESISTANT PROSTATE CANCER; CELL COMMUNICATION; CELL DENSITY; CELL FATE; CELL HETEROGENEITY; CELL HYBRIDIZATION; CELL MIGRATION; CLUSTER ANALYSIS; DRUG RESISTANCE; EPITHELIAL MESENCHYMAL TRANSITION; EPITHELIUM CELL; FEEDBACK SYSTEM; GENE REGULATORY NETWORK; HUMAN; INFLAMMATION; INTRACELLULAR SIGNALING; MESENCHYME CELL; METASTASIS; PHENOTYPE; PHENOTYPIC PLASTICITY; PLURIPOTENT STEM CELL; PROTEIN EXPRESSION; PROTEIN MOTIF;

EID: 84934297821     PISSN: None     EISSN: 2234943X     Source Type: Journal    
DOI: 10.3389/fonc.2015.00155     Document Type: Article

References (231)

1. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell (2011) 144:646-674. doi:10.1016/j.cell.2011.02.013
2. Christiansen JJ, Rajasekaran AK. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res (2006) 66:8319-26. doi:10.1158/0008-5472.CAN-06-0410
3. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest (2009) 119:1420-1428. doi:10.1172/JCI39104
4. Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science (2013) 342:1234850.
5. Gupta GP, Massagué J. Cancer metastasis: building a framework. Cell (2006) 127:679-695. doi:10.1016/j.cell.2006.11.001
6. Revenu C, Gilmour D. EMT 2.0: shaping epithelia through collective migration. Curr Opin Genet Dev (2009) 19:338-42. doi:10.1016/j.gde.2009.04.007
7. Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia (2010) 15:117-34. doi:10.1007/s10911-010-9178-9
8. Arnoux V, Côme C, Kusewitt DF, Hudson LG, Savagner P. "Cutaneous Wound Reepithelialization," in Rise and Fall of Epithelial Phenotype (Springer US), 111-134.
9. Klymkowsky MW, Savagner P. Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe. Am J Pathol (2009) 174:1588-93. doi:10.2353/ajpath.2009.080545
10. Lecharpentier A, Vielh P, Perez-Moreno P, Planchard D, Soria JC, Farace F. Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer. Br J Cancer (2011) 105:1338-1341. doi:10.1038/bjc.2011.405
11. Hou J-M, Krebs M, Ward T, Sloane R, Priest L, Hughes A, Clack G, Ranson M, Blackhall F, Dive C. Circulating Tumor Cells as a Window on Metastasis Biology in Lung Cancer. Am J Pathol (2011) 178:989-996. doi:10.1016/j.ajpath.2010.12.003
12. Armstrong AJ, Marengo MS, Oltean S, Kemeny G, Bitting RL, Turnbull JD, Herold CI, Marcom PK, George DJ, Garcia-Blanco MA. Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res (2011) 9:997-1007. doi:10.1158/1541-7786.MCR-10-0490
13. Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science (2013) 339:580-4. doi:10.1126/science.1228522
14. Joosse SA, Gorges TM, Pantel K. Biology, detection, and clinical implications of circulating tumor cells. EMBO Mol Med (2015) 7:1-11.
15. Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell (2014) 158:1110-1122. doi:10.1016/j.cell.2014.07.013
16. Grosse-Wilde A, Fouquier d' Herouei A, McIntosh E, Ertaylan G, Skupin A, Kuestner RE, del Sol A, Walters K-A, Huang S. Stemness of the hybrid epithelial/mesenchymal state in breast cancer and its association with poor survival. PLoS One (2015) in press
17. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol (2006) 7:131-42. doi:10.1038/nrm1835
18. Kumar S, Das A, Sen S. Extracellular matrix density promotes EMT by weakening cell-cell adhesions. Mol Biosyst (2014) 10:838-50. doi:10.1039/c3mb70431a
19. De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer (2013) 13:97-110. doi:10.1038/nrc3447
20. Brabletz S, Brabletz T. The ZEB/miR-200 feedback loop--a motor of cellular plasticity in development and cancer? EMBO Rep (2010) 11:670-7. doi:10.1038/embor.2010.117
21. Lu M, Jolly MK, Onuchic J, Ben-Jacob E. Toward Decoding the Principles of Cancer Metastasis Circuits. Cancer Res (2014) 74:4574-4587. doi:10.1158/0008-5472.CAN-13-3367
22. Chen L, Gibbons DL, Goswami S, Cortez MA, Ahn Y, Byers L a, Zhang X, Yi X, Dwyer D, Lin W, et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun (2014) 5:1-12. doi:10.1038/ncomms6241
23. Pecot C V, Rupaimoole R, Yang D, Akbani R, Ivan C, Lu C, Wu S, Han H-D, Shah MY, Rodriguez-Aguayo C, et al. Tumour angiogenesis regulation by the miR-200 family. Nat Commun (2013) 4:2427. doi:10.1038/ncomms3427
24. Sun Y, Daemen A, Hatzivassiliou G, Arnott D, Wilson C, Zhuang G, Gao M, Liu P, Boudreau A, Johnson L, et al. Metabolic and transcriptional profiling reveals pyruvate dehydrogenase kinase 4 as a mediator of epithelial-mesenchymal transition and drug resistance in tumor cells. (2014)1-14.
25. 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) 22:894-907. doi:10.1101/gad.1640608
26. Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, S paderna S, Brabletz T. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep (2008) 9:582-589. doi:10.1038/embor.2008.74
27. Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF, Goodall GJ. A double negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial mesenchymal transition. Cancer Res (2008) 68:7846-54. doi:10.1158/0008-5472.CAN-08-1942
28. Zhou JX, Huang S. Understanding gene circuits at cell-fate branch points for rational cell reprogramming. Trends Genet (2011) 27:55-62. doi:10.1016/j.tig.2010.11.002
29. Macía J, Widder S, Solé R. Why are cellular switches Boolean? General conditions for multistable genetic circuits. J Theor Biol (2009) 261:126-135. doi:10.1016/j.jtbi.2009.07.019
30. Andrecut M, Halley JD, Winkler DA, Huang S. A general model for binary cell fate decision gene circuits with degeneracy: indeterminacy and switch behavior in the absence of cooperativity. PLoS One (2011) 6:e19358. doi:10.1371/journal.pone.0019358
31. Guantes R, Poyatos JF. Multistable decision switches for flexible control of epigenetic differentiation. PLoS Comput Biol (2008) 4:e1000235. doi:10.1371/journal.pcbi.1000235
32. Cherry JL, Adler FR. How to make a biological switch. J Theor Biol (2000) 203:117-133. doi:10.1006/jtbi.2000.1068
33. Gardner TS, Cantor CR, Collins JJ. Construction of a genetic toggle switch in Escherichia coli. Nature (2000) 403:339-342. doi:10.1038/35002131
34. Huang S, Guo YP, May G, Enver T. Bifurcation dynamics in lineage-commitment in bipotent progenitor cells. Dev Biol (2007) 305:695-713. doi:10.1016/j.ydbio.2007.02.036
35. Balázsi G, Van Oudenaarden A, Collins JJ. Cellular decision making and biological noise: From microbes to mammals. Cell (2011) 144:910-925. doi:10.1016/j.cell.2011.01.030
36. Chin MT. Reprogramming cell fate: a changing story. Front Cell Dev Biol (2014) 2:1-6. doi:10.3389/fcell.2014.00046
37. Graf T, Enver T. Forcing cells to change lineages. Nature (2009) 462:587-594. doi:10.1038/nature08533
38. Pal M, Ghosh S, Bose I. Non-genetic heterogeneity, criticality and cell differentiation. Phys Biol (2015) 12:016001. doi:10.1088/1478-3975/12/1/016001
39. Tian X-J, Zhang H, Xing J. Coupled Reversible and Irreversible Bistable Switches Underlying TGFß-induced Epithelial to Mesenchymal Transition. Biophys J (2013) 105:1079-89. doi:10.1016/j.bpj.2013.07.011
40. Lu M, Jolly MK, Levine H, Onuchic JN, Ben-Jacob E. MicroRNA-based regulation of epithelial hybrid-mesenchymal fate determination. Proc Natl Acad Sci U S A (2013) 110:18174-9. doi:10.1073/pnas.1318192110
41. De Herreros AG, Baulida J. Cooperation, amplification, and feed- back in epithelial-mesenchymal transition. Biochim Biophys Acta (2012) 1825:223-8. doi:10.1016/j.bbcan.2012.01.003
42. Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, Hartwell K, Onder TT, Gupta PB, Evans KW, et al. Core epithelial-to-mesenchymal transition interactome gene expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A (2010) 107:15449-15454. doi:10.1073/pnas.1004900107
43. Gregory PA, Bracken CP, Smith E, Bert AG, Wright J a, Roslan S, Morris M, Wyatt L, Farshid G, Lim Y-Y, et al. An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol Biol Cell (2011) 22:1686-98. doi:10.1091/mbc.E11-02-0103
44. Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M, Mikulits W, Brabletz T, Strand D, Obrist P, et al. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene (2007) 26:6979- 6988. doi:10.1038/sj.onc.1210508
45. Zhang J, Tian X-J, Zhang H, Teng Y, Li R, Bai F, Elankumaran S, Xing J. TGF-ß-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci Signal (2014) 7:ra91.
46. Das S, Becker BN, Hoffmann FM, Mertz JE. Complete reversal of epithelial to mesenchymal transition requires inhibition of both ZEB expression and the Rho pathway. BMC Cell Biol (2009) 10:94. doi:10.1186/1471-2121-10-94
47. 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) 29:59-74. doi:10.1016/j.devcel.2014.03.006
48. Roca H, Hernandez J, Weidner S, McEachin RC, Fuller D, Sud S, Schumann T, Wilkinson JE, Zaslavsky A, Li H, et al. Transcription Factors OVOL1 and OVOL2 Induce the Mesenchymal to Epithelial Transition in Human Cancer. PLoS One (2013) 8:e76773. doi:10.1371/journal.pone.0076773
49. Roca H, Pande M, Huo JS, Hernandez J, Cavalcoli JD, Pienta KJ, McEachin RC. A bioinformatics approach reveals novel interactions of the OVOL transcription factors in the regulation of epithelial-mesenchymal cell reprogramming and cancer progression. BMC Syst Biol (2014) 8:29. doi:10.1186/1752-0509-8-29
50. Guo L, Chen C, Shi M, Wang F, Chen X, Diao D, Hu M, Yu M, Qian L, Guo N. Stat3-coordinated Lin-28-let-7-HMGA2 and miR-200-ZEB1 circuits initiate and maintain oncostatin M-driven epithelial-mesenchymal transition. Oncogene (2013) 32:5272-5282. doi:10.1038/onc.2012.573
51. Nair M, Bilanchone V, Ortt K, Sinha S, Dai X. Ovol1 represses its own transcription by competing with transcription activator c-Myb and by recruiting histone deacetylase activity. Nucleic Acids Res (2007) 35:1687-1697. doi:10.1093/nar/gkl1141
52. Jia D, Jolly MK, Boareto M, Parsana P, Mooney SM, Pienta KJ, Levine H, Ben-Jacob E. OVOL guides the epithelial-hybrid-mesenchymal transition. Oncotarget (2015)
53. Vannier C, Mock K, Brabletz T, Driever W. Zeb1 regulates E- cadherin and Epcam (epithelial cell adhesion molecule) expression to control cell behavior in early zebrafish development. J Biol Chem (2013) 288:18643-59. doi:10.1074/jbc.M113.467787
54. Kim NH, Kim HS, Li XY, Lee I, Choi HS, Kang SE, Cha SY, Ryu JK, Yoon D, Fearon ER, et al. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. J Cell Biol (2011) 195:417-433. doi:10.1083/jcb.201103097
55. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas M a, 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) 10:593-601. doi:10.1038/ncb1722
56. Peiró S, Escrivà M, Puig I, Barberà MJ, Dave N, Herranz N, Larriba MJ, Takkunen M, Francí C, Muñoz A, et al. Snail1 transcriptional repressor binds to its own promoter and controls its expression. Nucleic Acids Res (2006) 34:2077-2084. doi:10.1093/nar/gkl141
57. Hill L, Browne G, Tulchinsky E. ZEB/miR-200 feedback loop: at the crossroads of signal transduction in cancer. Int J Cancer (2013) 132:745-54. doi:10.1002/ijc.27708
58. Bintu L, Buchler NE, Garcia HG, Gerland U, Hwa T, Kondev J, Philips R. Transcriptional regulation by the numbers: models. Curr Opin Genet Dev (2005) 15:116-124.
59. Nyayanit D, Gadgil CJ. Mathematical modeling of combinatorial regulation suggests that apparent positive regulation of targets by miRNA could be an artifact resulting from competition for mRNA. RNA (2015) 21:307-19.
60. Mitarai N, Benjamin J-AM, Krishna S, Semsey S, Csiszovszki Z, Massé E, Sneppen K. Dynamic features of gene expression control by small regulatory RNAs. Proc Natl Acad Sci U S A (2009) 106:10655-10659. doi:10.1073/pnas.0901466106
61. Zhou P, Liu Z, Cai S, Wang R. Mechanisms generating bistability and oscillations in microRNA mediated motifs. Phys Rev E (2012) 85: doi:10.1103/PhysRevE.85.041916
62. Levine E, Ben Jacob E, Levine H. Target-specific and global effectors in gene regulation by MicroRNA. Biophys J (2007) 93:L52-L54. doi:10.1529/biophysj.107.118448
63. Schliekelman MJ, Taguchi A, Zhu J, Dai X, Rodriguez J, Celiktas M, Zhang Q, Chin A, Wong C, Wang H, et al. Molecular portraits of epithelial, mesenchymal and hybrid states in lung adenocarcinoma and their relevance to survival. Cancer Res (2015)canres-2535.
64. Keller PJ, Lin AF, Arendt LM, Klebba I, Jones AD, Rudnick JA, DiMeo TA, Gilmore H, Jefferson DM, Graham RA, et al. Mapping the cellular and molecular heterogeneity of normal and malignant breast tissues and cultured cell lines. Breast Cancer Res (2010) 12:R87. doi:10.1186/bcr2755
65. Goldman A, Majumder B, Dhawan A, Ravi S, Goldman D, Kohandel M, Majumder PK, Sengupta S. Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition. Nat Commun (2015) 6:6139. doi:10.1038/ncomms7139
66. Chéry L, Lam H, Coleman I, Lakely B, Coleman R, Larson S, Aguirre- ghiso JA, Xia J, Gulati R, Nelson PS, et al. Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways. Oncotarget (2014) 5:9939-9951.
67. Polioudaki H, Agelaki S, Chiotaki R, Politaki E, Mavroudis D, Matikas A, Georgoulias V, Theodoropoulos PA. Variable expression levels of keratin and vimentin reveal differential EMT status of circulating tumor cells and correlation with clinical characteristics and outcome of patients with metastatic breast cancer. BMC Cancer (2015) 15: doi:10.1186/s12885-015-1386-7
68. Frank SA, Rosner MR. Nonheritable cellular variability accelerates the evolutionary processes of cancer. PLoS Biol (2012) 10: doi:10.1371/journal.pbio.1001296
69. Tan TZ, Miow QH, Miki Y, Noda T, Mori S, Huang RY, Thiery JP. Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol Med (2014) 6:1279-1293. doi:10.15252/emmm.201404208
70. Bill R, Christofori G. The relevance of EMT in breast cancer metastasis: Correlation or causality? FEBS Lett (2015) doi:10.1016/j.febslet.2015.05.002
71. Jordan NV, Johnson GL, Abell AN. Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer. Cell Cycle (2011) 10:2865-2873. doi:10.4161/cc.10.17.17188
72. Yaswen P. Reinforcing targeted therapeutics with phenotypic stability factors. Cell Cycle (2015) 13:3818-3822. doi:10.4161/15384101.2014.985071
73. Huang B, Lu M, Jolly MK, Tsarfaty I, Onuchic J, Ben-Jacob E. The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition. Sci Rep (2014) 4: doi:10.1038/srep06449
74. Panková K, Rösel D, Novotnỳ M, Brábek J. The molecular mechanisms of transition between mesenchymal and amoeboid invasiveness in tumor cells. Cell Mol Life Sci (2010) 67:63-71. doi:10.1007/s00018-009-0132-1
75. Ben-Jacob E, Coffey DS, Levine H. Bacterial survival strategies suggest rethinking cancer cooperativity. Trends Microbiol (2012) 20:403-410. doi:10.1016/j.tim.2012.06.001
76. Bergert M, Chandradoss SD, Desai RA, Paluch E. Cell mechanics control rapid transitions between blebs and lamellipodia during migration. Proc Natl Acad Sci (2012) 109:14434-14439.
77. Chao Y, Wu Q, Acquafondata M, Dhir R, Wells A. Partial Mesenchymal to Epithelial Reverting Transition in Breast and Prostate Cancer Metastases. Cancer Microenviron (2011) 5:19-28. doi:10.1007/s12307-011-0085-4
78. Friedl P, Wolf K. Plasticity of cell migration: a multiscale tuning model. J Cell Biol (2010) 188:11-9. doi:10.1083/jcb.200909003
79. Wolf K, Wu YI, Liu Y, Geiger J, Tam E, Overall C, Stack MS, Friedl P. Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat Cell Biol (2007) 9:893-904. doi:10.1038/ncb1616
80. Hegerfeldt Y, Tusch M, Bröcker E-B, Friedl P. Collective cell movement in primary melanoma explants: plasticity of cell-cell interaction, beta1-integrin function, and migration strategies. Cancer Res (2002) 62:2125-2130.
81. Parri M, Chiarugi P. Rac and Rho GTPases in cancer cell motility control. Cell Commun Signal (2010) 8:23. doi:10.1186/1478-811X-8-23
82. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol (2014) 15:178-196. doi:10.1038/nrm3758.Molecular
83. Wang H, Hanash SM, Schliekelman MJ, Gibbons DL, Wong C-H, Ungewiss C, Kurie JM, Rizvi ZH, Zhang Q, Ahn Y-H, et al. Targets of the Tumor Suppressor miR-200 in Regulation of the Epithelial-Mesenchymal Transition in Cancer. Cancer Res (2011) 71:7670-7682. doi:10.1158/0008-5472.CAN-11-0964
84. Kim D, Kim S, Jin E-J, Park HM, Sonn J, Song J, Chun C-H. MicroRNA-34a Modulates Cytoskeletal Dynamics through Regulating RhoA/Rac1 Cross-talk in Chondroblasts. J Biol Chem (2012) 287:12501-12509. doi:10.1074/jbc.M111.264382
85. Elson-Schwab I, Lorentzen A, Marshall CJ. MicroRNA-200 family members differentially regulate morphological plasticity and mode of melanoma cell invasion. PLoS One (2010) 5: doi:10.1371/journal.pone.0013176
86. Sailem H, Bousgouni V, Cooper S, Bakal C. Cross-talk between Rho and Rac GTPases drives deterministic exploration of cellular shape space and morphological heterogeneity. Open Biol (2014) 4:130132. doi:10.1098/rsob.130132
87. Jilkine A, Marée AFM, Edelstein-Keshet L. Mathematical model for spatial segregation of the Rho-family GTPases based on inhibitory crosstalk. Bull Math Biol (2007) 69:1943-1978. doi:10.1007/s11538-007-9200-6
88. Chauhan BK, Lou M, Zheng Y, Lang R a. Balanced Rac1 and RhoA activities regulate cell shape and drive invagination morphogenesis in epithelia. Proc Natl Acad Sci (2011) 108:18289-18294. doi:10.1073/pnas.1108993108
89. Futterman MA, García AJ, Zamir EA. Evidence for partial epithelial-to-mesenchymal transition (pEMT) and recruitment of motile blastoderm edge cells during avian epiboly. Dev Dyn (2011) 240:1502-1511. doi:10.1002/dvdy.22607
90. Johnen N, Francart M-E, Thelen N, Cloes M, Thiry M. Evidence for a partial epithelial mesenchymal transition in postnatal stages of rat auditory organ morphogenesis. Histochem Cell Biol (2012) 138:477-88. doi:10.1007/s00418-012-0969-5
91. Ribeiro AS, Paredes J. P-Cadherin Linking Breast Cancer Stem Cells and Invasion: A Promising Marker to Identify an "Intermediate/Metastable" EMT State. Front Oncol (2015) 4:1-6. doi:10.3389/fonc.2014.00371
92. Welch-Reardon KM, Ehsan SM, Wang K, Wu N, Newman AC, Romero-Lopez M, Fong AH, George SC, Edwards RA, Hughes CCW. Angiogenic sprouting is regulated by endothelial cell expression of Slug. J Cell Sci (2014) 127:2017-28. doi:10.1242/jcs.143420
93. Leopold PL, Vincent J, Wang H. A comparison of epithelial-to-mesenchymal transition and re epithelialization. Semin Cancer Biol (2012) 22:471-83. doi:10.1016/j.semcancer.2012.07.003
94. Yan C, Grimm W a, Garner WL, Qin L, Travis T, Tan N, Han Y-P. Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol (2010) 176:2247-2258. doi:10.2353/ajpath.2010.090048
95. Leroy P, Mostov KE. Slug Is Required for Cell Survival during Partial Epithelial-Mesenchymal Transition of HGF-induced tubulogenesis. J Cell Sci (2007) 18:1943-1952. doi:10.1091/mbc.E06
96. Hudson LG, Newkirk KM, Chandler HL, Choi C, Fossey SL, Parent AE, Kusewitt DF. Cutaneous wound reepithelialization is compromised in mice lacking functional Slug (Snai2). J Dermatol Sci (2009) 56:19-26. doi:10.1016/j.jdermsci.2009.06.009
97. Niessen K, Fu Y, Chang L, Hoodless P a, McFadden D, Karsan A. Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J Cell Biol (2008) 182:315-25. doi:10.1083/jcb.200710067
98. Lee K, Gjorevski N, Boghaert E, Radisky DC, Nelson CM. Snail1, Snail2, and E47 promote mammary epithelial branching morphogenesis. EMBO J (2011) 30:2662-2674. doi:10.1038/emboj.2011.159
99. Savagner P, Kusewitt DF, Carver EA, Magnino F, Choi C, Gridley T, Hudson LG. Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J Cell Physiol (2005) 202:858-866. doi:10.1002/jcp.20188
100. Friedl P, Locker J, Sahai E, Segall JE. Classifying collective cancer cell invasion. Nat Cell Biol (2012) 14:777-783. doi:10.1038/ncb2548
101. Strauss R, Sova P, Liu Y, Zong YL, Tuve S, Pritchard D, Brinkkoetter P, Möller T, Wildner O, Pesonen S, et al. Epithelial phenotype confers resistance of ovarian cancer cells to oncolytic adenoviruses. Cancer Res (2009) 69:5115-5125. doi:10.1158/0008-5472.CAN-09-0645
102. Huang RY-J, Wong MK, Tan TZ, Kuay KT, Ng AHC, Chung VY, Chu Y-S, Matsumura N, Lai H-C, Lee YF, et al. An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530). Cell Death Dis (2013) 4:e915. doi:10.1038/cddis.2013.442
103. Sampson VB, David JM, Puig I, Patil PU, de Herreros AG, Thomas G V., Rajasekaran AK. Wilms' tumor protein induces an epithelial-mesenchymal hybrid differentiation state in clear cell renal cell carcinoma. PLoS One (2014) 9:e102041. doi:10.1371/journal.pone.0102041
104. Rhim AD, Mirek ET, Aiello NM, Maitra A, Jennifer M, Mccallister F, Reichert M, Beatty GL, Anil K, Vonderheide RH, et al. EMT and dissemination precede pancreatic tumor formation. Cell (2013) 148:349-361. doi:10.1016/j.cell.2011.11.025.EMT
105. Ruscetti M, Quach B, Dadashian EL, Mulholland DJ, Hong W. Tracking and Functional Characterization of Epithelial-Mesenchymal Transition and Mesenchymal Tumor Cells During Prostate Cancer Metastasis. Cancer Res (2015)canres-3476. doi:10.1158/0008-5472.CAN-14- 3476
106. Sarrio D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J. Epithelial mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Rese (2008) 68:989-997. doi:10.1158/0008-5472.CAN-07-2017
107. Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res (2010) 12:R68. doi:10.1186/bcr2635
108. Hendrix MJ, Seftor EA, Seftor RE, Trevor KT. Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior. Am J Pathol (1997) 150:483-495.
109. Thomas PA, Kirschmann DA, Cerhan JR, Folberg R, Seftor EA, Sellers TA, Hendrix MJC. Association between keratin and vimentin expression, malignant phenotype, and survival in postmenopausal breast cancer patients. Clin Cancer Res (1999) 5:2698-2703.
110. Ramaekers FC, Haag D, Kant A, Moesker O, Jap PH, Vooijs GP. Coexpression of keratin- and vimentin-type intermediate filaments in human metastatic carcinoma cells. Proc Natl Acad Sci U S A (1983) 80:2618-2622. doi:10.1073/pnas.80.9.2618
111. Hendrix MJ, Seftor EA, Chu Y, Seftor REB, Nagle RB, McDaniel KM, Leong SPL, Yohem KH, Leibovitz AM, Meyskens FLJ, et al. Coexpression of Vimentin and Keratins by Human Melanoma Tumor Cells: Correlation with invasive and metastatic potential. J Natl Cancer Inst (1992) 84:165-174.
112. Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol (2006) 19:264-271. doi:10.1038/modpathol.3800528
113. Wu S, Liu S, Liu Z, Huang J, Pu X, Li J, Yang D, Deng H, Yang N, Xu J. Classification of Circulating Tumor Cells by Epithelial-Mesenchymal Transition Markers. PLoS One (2015) 10:e0123976. doi:10.1371/journal.pone.0123976
114. Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, Priest LJC, Greystoke A, Zhou C, Morris K, 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 (2012) 30:525-532. doi:10.1200/JCO.2010.33.3716
115. Ilie M, Hofman V, Long-Mira E, Selva E, Vignaud J-M, Padovani B, Mouroux J, Marquette C-H, Hofman P. "Sentinel" Circulating Tumor Cells Allow Early Diagnosis of Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease. PLoS One (2014) 9:e111597. doi:10.1371/journal.pone.0111597
116. Liotta LA, Klelnerman J, Saldel GM. The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res (1976) 36:889-894.
117. Fidler IJ. The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Eur J Cancer (1973) 9:223-227. doi:10.1016/S0014-2964(73)80022-2
118. Hugo H, Ackland LM, Blick T, Lawrence MG, Clementa JA, Williams ED, Thompson EW. Epithelial-Mesenchymal and Mesenchymal-Epithelial Transitions in Carcinoma Progression. J Cell Physiol (2007) 213:374-383. doi:10.1002/jcp.21223
119. Alix-Panabières C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer (2014) 14:623. doi:10.1038/nrc3686
120. Ting DT, Wittner BS, Ligorio M, Vincent Jordan N, Shah AM, Miyamoto DT, Aceto N, Bersani F, Brannigan BW, Xega K, et al. Single-Cell RNA Sequencing Identifies Extracellular Matrix Gene Expression by Pancreatic Circulating Tumor Cells. Cell Rep (2014)1905-1918. doi:10.1016/j.celrep.2014.08.029
121. Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A, Schillert A, Vogel V, Klein C, Saini M, Bäuerle T, Wallwiener M, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol (2013) 31:539-44. doi:10.1038/nbt.2576
122. Cayrefourcq L, Mazard T, Joosse S, Solassol J, Ramos J, Assenat E, Schumacher U, Costes V, Maudelonde T, Pantel K, et al. Establishment and Characterization of a Cell Line from Human Circulating Colon Cancer Cells. Cancer Res (2015) 75:892-902. doi:10.1158/0008-5472.CAN-14- 2613
123. Strauss R, Li Z-Y, Liu Y, Beyer I, Persson J, Sova P, Möller T, Pesonen S, Hemminki A, Hamerlik P, et al. Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity. PLoS One (2011) 6:e16186. doi:10.1371/journal.pone.0016186
124. Plaks V, Kong N, Werb Z. The Cancer Stem Cell Niche: How Essential Is the Niche in Regulating Stemness of Tumor Cells? Cell Stem Cell (2015) 16:225-238. doi:http://dx.doi.org/10.1016/j.stem.2015.02.015
125. Gupta PB, Fillmore CM, Jiang G, Shapira SD, Tao K, Kuperwasser C, Lander ES. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell (2011) 146:633- 644. doi:10.1016/j.cell.2011.07.026
126. Yang G, Quan Y, Wang W, Fu Q, Wu J, Mei T, Li J, Tang Y, Luo C, Ouyang Q, et al. Dynamic equilibrium between cancer stem cells and non-stem cancer cells in human SW620 and MCF-7 cancer cell populations. Br J Cancer (2012) 106:1512-9. doi:10.1038/bjc.2012.126
127. Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation o f breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci U S A (2011) 108:1397-402. doi:10.1073/pnas.1018898108
128. Enderling H. Cancer stem cells: small subpopulation or evolving fraction? Integr Biol (Camb) (2014) doi:10.1039/c4ib00191e
129. Csermely P, Hódsági J, Korcsmáros T, Módos D, Perez-Lopez áR, Szalay K, Veres D V., Lenti K, Wu LY, Zhang XS. Cancer stem cells display extremely large evolvability: alternating plastic and rigid networks as a potential Mechanism Network models, novel therapeutic target strategies, and the contributions of hypoxia, inflammation and cellular senescence. Semin Cancer Biol (2015) 30:42-51. doi:10.1016/j.semcancer.2013.12.004
130. Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell (2008) 133:704-715. doi:10.1016/j.cell.2008.03.027
131. Morel A-P, Lièvre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One (2008) 3:e2888. doi:10.1371/journal.pone.0002888
132. Scheel C, Weinberg RA. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin Cancer Biol (2012) 22:396-403. doi:10.1016/j.semcancer.2012.04.001
133. Ombrato L, Malanchi I. The EMT Universe: Space between Cancer Cell Dissemination and Metastasis Initiation. Crit Rev Oncog (2014) 19:349-361.
134. Celià-Terrassa T, Meca-Cortés ó, Mateo F, De Paz AM, Rubio N, Arnal-Estapé A, Ell BJ, Bermudo R, Díaz A, Guerra-Rebollo M, et al. Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J Clin Invest (2012) 122:1849-1868. doi:10.1172/JCI59218
135. 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) 22:709-724. doi:10.1016/j.ccr.2012.10.012
136. 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) 22:725-736. doi:10.1016/j.ccr.2012.09.022
137. Tsuji T, Ibaragi S, Shima K, Hu MG, Katsurano M, Sasaki A, Hu GF. Epithelial-mesenchymal transition induced by growth suppressor p12 CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth. Cancer Res (2008) 68:10377-10386. doi:10.1158/0008- 5472.CAN-08-1444
138. Samavarchi-Tehrani P, Golipour A, David L, Sung H-K, Beyer TA, Datti A, Woltjen K, Nagy A, Wrana JL. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell (2010) 7:64-77. doi:10.1016/j.stem.2010.04.015
139. Li R, Liang J, Ni S, Zhou T, Qing X, Li H, He W, Chen J, Li F, Zhuang Q, et al. A mesenchymal1064 to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell (2010) 7:51-63. doi:10.1016/j.stem.2010.04.014
140. Jolly MK, Huang B, Lu M, Mani SA, Levine H, Ben-Jacob E. Towards elucidating the connection between epithelial-mesenchymal transitions and stemness. J R Soc Interface (2014) 11:20140962. doi:10.1098/rsif.2014.0962
141. Yovchev MI, Grozdanov PN, Zhou H, Racherla H, Guha C, Dabeva MD. Identification of adult hepatic progenitor cells capable of repopulating injured rat liver. Hepatology (2008) 47:636-47. doi:10.1002/hep.22047
142. Conigliaro A, Amicone L, Costa V, De Santis Puzzonia M, Mancone C, Sacchetti B, Cicchini C, Garibaldi F, Brenner DA, Kisseleva T, et al. Evidence for a common progenitor of epithelial and mesenchymal components of the liver. Cell Death Differ (2013) 20:1116-23. doi:10.1038/cdd.2013.49
143. Cicchini C, Amicone L, Alonzi T, Marchetti A, Mancone C, Tripodi M. Molecular mechanisms controlling the phenotype and the EMT/MET dynamics of hepatocyte. Liver Int (2015) 35:302- 310. doi:10.1111/liv.12577
144. Choi SS, Diehl AM. Epithelial-to-Mesenchymal Transitions in the Liver. Hep (2009) 50:2007- 2013. doi:10.1002/hep.23196
145. Swetha G, Chandra V, Phadnis S, Bhonde R. Glomerular parietal epithelial cells of adult murine kidney undergo EMT to generate cells with traits of renal progenitors. J Cell Mol Med (2011) 15:396-413. doi:10.1111/j.1582-4934.2009.00937.x
146. Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med (2013) 19:1438-49. doi:10.1038/nm.3336
147. Das R, Gregory PA, Hollier BG, Tilley WD, Selth LA. Epithelial plasticity in prostate cancer: principles and clinical perspectives. Trends Mol Med (2014) 20:643-651. doi:10.1016/j.molmed.2014.09.004
148. Ansieau S, Collin G, Hill L. EMT or EMT-Promoting Transcription Factors, Where to Focus the Light? Front Oncol (2014) 4: doi:10.3389/fonc.2014.00353
149. Strauss R, Hamerlik P, Lieber A, Bartek J. Regulation of Stem Cell Plasticity: Mechanisms and Relevance to Tissue Biology and Cancer. Mol Ther (2012) 20:887-897. doi:10.1038/mt.2012.2
150. Liu S, Cong Y, Wang D, Sun Y, Deng L, Liu Y, Martin-Trevino R, Shang L, McDermott SP, Landis MD, et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports (2014) 2:78-91. doi:10.1016/j.stemcr.2013.11.009
151. Biddle A, Liang X, Gammon L, Fazil B, Harper LJ, Emich H, Costea DE, Mackenzie IC. Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer R es (2011) 71:5317-5326. doi:10.1158/0008- 5472.CAN-11-1059
152. Brabletz T. To differentiate or not - routes towards metastasis. Nat Rev Cancer (2012) 12:425- 436. doi:10.1038/nrc3265
153. Barriere G, Fici P, Gallerani G, Fabbri F, Rigaud M. Epithelial Mesenchymal Transition: a double edged sword. Clin Transl Med (2015) 4:4-9. doi:10.1186/s40169-015-0055-4
154. Alix-Panabières C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer (2014) 14:623. doi:10.1038/nrc3686
155. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM. Identification of pancreatic cancer stem cells. Cancer Res (2007) 67:1030-1037. doi:10.1158/0008-5472.CAN-06-2030
156. Zhang C, Li C, He F, Cai Y, Yang H. Identification of CD44+CD24+ gastric cancer stem cells. J Cancer Res Clin Oncol (2011) 137:1679-1686. doi:10.1007/s00432-011-1038-5
157. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol (2008) 8:726-736. doi:10.1038/nri2395
158. Sleeman KE, Kendrick H, Ashworth A, Isacke CM, Smalley MJ. CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells. Breast Cancer Res (2006) 8:R7. doi:10.1186/bcr1371
159. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci (2003) 100:3983-3988.
160. Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res (2008) 10:R25. doi:10.1186/bcr1982
161. Azzam DJ, Zhao D, Sun J, Minn AJ, Ranganathan P, Drews-Elger K, Han X, Picon-Ruiz M, Gilbert CA, Wander SA, et al. Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in γ-secretase inhibitor drug responses. EMBO Mol Med (2013) 5:1502-1522. doi:10.1002/emmm.201302558
162. Bhat-Nakshatri P, Appaiah H, Ballas C, Pick-Franke P, Goulet R, Badve S, Srour EF, Nakshatri H. SLUG/SNAI2 and tumor necrosis factor generate breast cells with CD44+/CD24- phenotype. BMC Cancer (2010) 10:411. doi:10.1186/1471-2407-10-411
163. Yang C-H, Wang H-L, Lin Y-S, Kumar KPS, Lin H-C, Chang C-J, Lu C-C, Huang T-T, Martel J, Ojcius DM, et al. Identification of CD24 as a cancer stem cell marker in human nasopharyngeal carcinoma. PLoS One (2014) 9:e99412. doi:10.1371/journal.pone.0099412
164. Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L, Chiarugi P. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial mesenchymal transition and cancer stemness. Cancer Res (2010) 70:6945-6956. doi:10.1158/0008-5472.CAN-10-0785
165. Yang KR, Mooney SM, Zarif JC, Coffey DS, Taichman RS, Pienta KJ. Niche inheritance: A cooperative pathway to enhance cancer cell fitness though ecosystem engineering. J Cell Biochem (2014) 115:1478-1485. doi:10.1002/jcb.24813
166. Chen W-J, Ho C-C, Chang Y-L, Chen H-Y, Lin C-A, Ling T-Y, Yu S-L, Yuan S-S, Chen Y-JL, Lin C-Y, et al. Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat Commun (2014) 5:3472. doi:10.1038/ncomms4472
167. Sanità P, Capulli M, Teti A, Galatioto GP, Vicentini C, Chiarugi P, Bologna M, Angelucci A. Tumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression. BMC Cancer (2014) 14:154. doi:10.1186/1471-2407-14-154
168. Duda DG, Duvyerman AMMJ, Kohno M, Snuderi M, Snuderi M, Steller EJA, Fukumura D, Jain RK. Malignant cells facilitate lung metastasis by bringing their own soil. Proc Natl Acad Sci (2007) 107:21677-21682. doi:10.1073/pnas.1016234107
169. De Herreros AG. Epithelial to mesenchymal transition in tumor cells as consequence of phenotypic instability. Front Cell Dev Biol (2014) 2: doi:10.3389/fcell.2014.00071
170. Espinoza I, Miele L. Deadly crosstalk: Notch signaling at the intersection of EMT and cancer stem cells. Cancer Lett (2013) 341:41-45. doi:10.1016/j.canlet.2013.08.027
171. Li D, Masiero M, Banham AH, Harris AL. The notch ligand JAGGED1 as a target for anti-tumor therapy. Front Oncol (2014) 4: doi:10.3389/fonc.2014.00254
172. Boareto M, Jolly MK, Lu M, Onuchic JN, Clementi C, Ben-Jacob E. Jagged-Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype. Proc Natl Acad Sci (2015) 112:E402-E409. doi:10.1073/pnas.1416287112
173. Jolly MK, Boareto M, Lu M, Onuchic JN, Clementi C, Ben-Jacob E. Operating Principles of Notch-Delta-Jagged module of cell-cell communication. New J Phys (2015) 17:055021.
174. Lu J, Ye X, Fan F, Xia L, Bhattacharya R, Bellister S, Tozzi F, Sceusi E, Zhou Y, Tachibana I, et al. Endothelial Cells Promote the Colorectal Cancer Stem Cell Phenotype through a Soluble Form of Jagged-1. Cancer Cell (2013) 23:171-185. doi:10.1016/j.ccr.2012.12.021
175. Yamamoto M, Taguchi Y, Ito-Kureha T, Semba K, Yamaguchi N, Inoue J. NF-κB non-cell autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype. Nat Commun (2013) 4: doi:10.1038/ncomms3299
176. Sethi N, Dai X, Winter CG, Kang Y. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell (2011) 19:192- 205. doi:10.1016/j.ccr.2010.12.022
177. Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, Ceccarelli C, Santini D, Paterini P, Marcu KB, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest (2007) 117:3988-4002. doi:10.1172/JCI32533
178. Shaya O, Sprinzak D. From Notch signaling to fine-grained patterning: Modeling meets experiments. Curr Opin Genet Dev (2011) 21:732-739. doi:10.1016/j.gde.2011.07.007
179. Petrovic J, Formosa-Jordan P, Luna-Escalante JC, Abelló G, Ibañes M, Neves J, Giraldez F. Ligand-dependent Notch signaling strength orchestrates lateral induction and lateral inhibition in the developing inner ear. Development (2014) 141:2313-24. doi:10.1242/dev.108100
180. Owen MR, Sherratt JA, Wearing HJ. Lateral induction by juxtacrine signaling is a new mechanism for pattern formation. Dev Biol (2000) 217:54-61. doi:10.1006/dbio.1999.9536
181. Hartman BH, Reh TA, Bermingham-McDonogh O. Notch signaling specifies prosensory domains via lateral induction in the developing mammalian inner ear. Proc Natl Acad Sci U S A (2010) 107:15792-15797. doi:10.1073/pnas.1002827107
182. Chigurupati S, Arumugam T V, Son TG, Lathia JD, Jameel S, Mughal MR, Tang S-C, Jo D-G, Camandola S, Giunta M, et al. Involvement of notch signaling in wound healing. PLoS One (2007) 2:e1167. doi:10.1371/journal.pone.0001167
183. Brabletz S, Bajdak K, Meidhof S, Burk U, Niedermann G, Firat E, Wellner U, Dimmler A, Faller G, Schubert J, et al. The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells. EMBO J (2011) 30:770-82. doi:10.1038/emboj.2010.349
184. De Antonellis P, Medaglia C, Cusanelli E, Andolfo I, Liguori L, De Vita G, Carotenuto M, Bello A, Formiggini F, Galeone A, et al. MiR-34a targeting of Notch ligand delta-like 1 impairs CD15+/CD133+ tumor-propagating cells and supports neural differentiation in medulloblastoma. PLoS One (2011) 6:e24584. doi:10.1371/journal.pone.0024584
185. Bu P, Chen K-Y, Chen JH, Wang L, Walters J, Shin YJ, Goerger JP, Sun J, Witherspoon M, Rakhilin N, et al. A microRNA miR-34a-regulated bimodal switch targets notch in colon cancer stem cells. Cell Stem Cell (2013) 12:602-15. doi:10.1016/j.stem.2013.03.002
186. Sahlgren C, Gustafsson M V, Jin S, Poellinger L, Lendahl U. Notch signaling mediates hypoxia induced tumor cell migration and invasion. Proc Natl Acad Sci U S A (2008) 105:6392-7. doi:10.1073/pnas.0802047105
187. Niessen K, Fu Y, Chang L, Hoodless P a, McFadden D, Karsan A. Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J Cell Biol (2008) 182:315-25. doi:10.1083/jcb.200710067
188. Duluc D, Delneste Y, Tan F, Moles M-P, Grimaud L, Lenoir J, Preisser L, Anegon I, Catala L, Ifrah N, et al. Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. Blood (2007) 110:4319-30. doi:10.1182/blood-2007-02-072587
189. Johnston DA, Dong B, Hughes CCW. TNF induction of jagged-1 in endothelial cells is NFkappaB-dependent. Gene (2009) 435:36-44. doi:10.1016/j.gene.2009.01.003
190. Benedito R, Roca C, Sörensen I, Adams S, Gossler A, Fruttiger M, Adams RH. The Notch Ligands Dll4 and Jagged1 Have Opposing Effects on Angiogenesis. Cell (2009) 137:1124-1135. doi:10.1016/j.cell.2009.03.025
191. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability. Carcinogenesis (2009) 30:1073-1081. doi:10.1093/carcin/bgp127
192. McGuire MF, Enderling H, Wallace DI, Batra J, Jordan M, Kumar S, Panetta JC, Pasquier E. Formalizing an integrative, multidisciplinary cancer therapy discovery workflow. Cancer Res (2013) 73:6111-6117. doi:10.1158/0008-5472.CAN-13-0310
193. Enderling H, Hahnfeldt P, Hlatky L, Almog N. Systems biology of tumor dormancy: Linking biology and mathematics on multiple scales to improve cancer therapy. Cancer Res (2012) 72:2172-2175. doi:10.1158/0008-5472.CAN-11-3269
194. Marchini S, Fruscio R, Clivio L, Beltrame L, Porcu L, Nerini IF, Cavalieri D, Chiorino G, Cattoretti G, Mangioni C, et al. Resistance to platinum-based chemotherapy is associated with epithelial to mesenchymal transition in epithelial ovarian cancer. Eur J Cancer (2012) 49:520- 530. doi:10.1016/j.ejca.2012.06.026
195. Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, Gallick GE, Logsdon CD, McConkey DJ, Choi W. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res (2009) 69:5820-5828. doi:10.1158/0008-5472.CAN- 08-2819
196. Witta SE, Gemmill RM, Hirsch FR, Coldren CD, Hedman K, Ravdel L, Helfrich B, Dziadziuszko R, Chan DC, Sugita M, et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res (2006) 66:944-950. doi:10.1158/0008-5472.CAN-05-1988
197. May CD, Sphyris N, Evans KW, Werden SJ, Guo W, Mani SA. Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression. Breast Cancer Res (2011) 13:202. doi:10.1186/bcr2789
198. André F, Zielinski CC. Optimal strategies for the treatment of metastatic triple-negative breast cancer with currently approved agents. Ann Oncol (2012) 23:vi46-vi51. doi:10.1093/annonc/mds195
199. Vadgama J V., Wu Y, Ginther C, Kim J, Mosher N, Chung S, Slamon D. Expression of Wnt3 activates Wnt/ß-catenin pathway and promotes EMT-like phenotype in trastuzumab resistant HER2-overexpressing breast cancer cells. Mol Cancer Res (2012) 10:1597-606. doi:10.1158/1541-7786.MCR-12-0155-T
200. Hiscox S, Jiang WG, Obermeier K, Taylor K, Morgan L, Burmi R, Barrow D, Nicholson RI. Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of ß- catenin phosphorylation. Int J Cancer (2006) 118:290-301. doi:10.1002/ijc.21355
201. Bastos LGDR, de Marcondes PG, de-Freitas-Junior JCM, Leve F, Mencalha AL, de Souza WF, de Araujo WM, Tanaka MN, Abdelhay ESFW, Morgado-Díaz JA. Progeny From Irradiated Colorectal Cancer Cells Acquire an EMT- Like Phenotype and A ctivate Wnt/ß-Catenin Pathway. J Cell Biochem (2014) 115:2175-2187. doi:10.1002/jcb.24896
202. Nieto MA, Cano A. Seminars in Cancer Biology The epithelial-mesenchymal transition under control: Global programs to regulate epithelial plasticity. (2012) 22:361-368.
203. Dvorak H. Tumors: wounds that do not heal. N Engl J Med (1986) 315:1650-9. doi:10.1056/NEJM198612253152606
204. Zhu H, Bhaijee F, Ishaq N, Pepper DJ, Backus K, Brown AS, Zhou X, Miele L. Correlation of Notch1, pAKT and nuclear NF-κB expression in triple negative breast cancer. Am J Cancer Res (2013) 3:230-9.
205. Schaue D, Micewicz ED, Ratikan J a., Xie MW, Cheng G, McBride WH. Radiation and Inflammation. Semin Radiat Oncol (2015) 25:4-10. doi:10.1016/j.semradonc.2014.07.007
206. Multhoff G, Radons J. Radiation, inflammation, and immune responses in cancer. Front Oncol (2012) 2: doi:10.3389/fonc.2012.00058
207. Torres MA, Pace TW, Liu T, Felger JC, Mister D, Gregory H. Predictors of Depression in Breast Cancer Patients Treated With Radiation: Role of Prior Chemotherapy and Nuclear Factor Kappa B. Cancer (2013) 119:1951-1959. doi:10.1002/cncr.28003
208. Wang Z, Li Y, Kong D, Banerjee S, Ahmad A, Azmi AS, Ali S, Abbruzzese JL, Gallick GE, Sarkar FH. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res (2009) 69:2400-7. doi:10.1158/0008-5472.CAN-08-4312
209. Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (1995) 154:8-20. doi:10.1159/000147748
210. Corallino S, Malabarba MG, Zobel M, Di Fiore PP, Scita G. Epithelial-to-Mesenchymal Plasticity Harnesses Endocytic Circuitries. Front Oncol (2015) 5: doi:10.3389/fonc.2015.00045
211. Pinto CA, Widodo E, Waltham M, Thompson EW. Breast cancer stem cells and epithelial mesenchymal plasticity-Implications for chemoresistance. Cancer Lett (2013) 341:56-62. doi:10.1016/j.canlet.2013.06.003
212. McInnes LM, Jacobson N, Redfern A, Dowling A, Thompson EW, Saunders CM. Clinical Implications of Circulating Tumor Cells of Breast Cancer Patients: Role of Epithelial Mesenchymal Plasticity. Front Oncol (2015) 5: doi:10.3389/fonc.2015.00042
213. Theveneau E, Mayor R. Collective cell migration of epithelial and mesenchymal cells. Cell Mol Life Sci (2013) 70:3481-3492. doi:10.1007/s00018-012-1251-7
214. Rogers CD, Saxena A, Bronner ME. Sip1 mediates an E-cadherin-to-N-cadherin switch during cranial neural crest EMT. J Cell Biol (2013) 203:835-847. doi:10.1083/jcb.201305050
215. Huang RY-J, Wong MK, Tan TZ, Kuay KT, Ng a HC, Chung VY, Chu Y-S, Matsumura N, Lai H-C, Lee YF, et al. An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530). Cell Death Dis (2013) 4:e915. doi:10.1038/cddis.2013.442
216. Rodriguez FJ, Lewis-Tuffin LJ, Anastasiadis PZ. E-cadherin's dark side: possible role in tumor progression. Biochim Biophys Acta (2012) 1826:23-31. doi:10.1016/j.bbcan.2012.03.002
217. Bednarz-Knoll N, Alix-Panabières C, Pantel K. Plasticity of disseminating cancer cells in patients with epithelial malignancies. Cancer Metastasis Rev (2012) 31:673-87. doi:10.1007/s10555-012- 9370-z
218. Chouaib S, Janji B, Tittarelli A, Eggermont A, Thiery JP. Tumor Plasticity Interferes with Anti- Tumor Immunity. Crit Rev Immunol (2014) 34:91-102. doi:10.1615/CritRevImmunol.2014010183
219. Cai X, Dai Z, Reeves RS, Caballero-Benitez A, Duran KL, Delrow JJ, Porter PL, Spies T, Groh V. Autonomous Stimulation of Cancer Cell Plasticity by the Human NKG2D Lymphocyte Receptor Coexpressed with Its Ligands on Cancer Cells. PLoS One (2014) 9:e108942. doi:10.1371/journal.pone.0108942
220. Zuo J, Ishikawa T, Boutros S, Xiao Z, Humtsoe JO, Kramer RH. Bcl-2 overexpression induces a partial epithelial to mesenchymal transition and promotes squamous carcinoma cell invasion and metastasis. Mol Cancer Res (2010) 8:170-182. doi:10.1158/1541-7786.MCR-09-0354
221. Mitra A, Menezes ME, Shevde LA, Samant RS. DNAJB6 induces degradation of ß-catenin and causes partial reversal of mesenchymal phenotype. J Biol Chem (2010) 285:24686-24694. doi:10.1074/jbc.M109.094847
222. Morbini P, Inghilleri S, Campo I, Oggionni T, Zorzetto M, Luisetti M. Incomplete expression of epithelial-mesenchymal transition markers in idiopathic pulmonary fibrosis. Pathol Res Pract (2011) 207:559-567. doi:10.1016/j.prp.2011.06.006
223. Damonte P, Gregg JP, Borowsky AD, Keister B a, Cardiff RD. EMT tumorigenesis in the mouse mammary gland. Lab Invest (2007) 87:1218-1226. doi:10.1038/labinvest.3700683
224. Umbreit C, Flanjak J, Weiss C, Erben P, Aderhold C, Faber A, Stern-straeter J, Hoermann K, Schultz JD. Incomplete Epithelial-Mesenchymal Transition in p16-positive Squamous Cell Carcinoma Cells Correlates with ß-Catenin Expression. Anticancer Res (2014) 34:7061-7070.
225. Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol (2010) 21:1819-1834. doi:10.1681/ASN.2010080793
226. Gopal SK, Greening DW, Mathias RA, Ji H, Rai A, Chen M, Zhu H, Simpson RJ. YBX1 / YB-1 induces partial EMT and tumourigenicity through secretion of angiogenic factors into the extracellular microenvironment. Oncotarget (2015)
227. Lundgren K, Nordenskjöld B, Landberg G. Hypoxia, Snail and incomplete epithelial mesenchymal transition in breast cancer. Br J Cancer (2009) 101:1769-1781. doi:10.1038/sj.bjc.6605369
228. Schuetz AN, Rubin BP, Goldblum JR, Shehata B, Weiss SW, Liu W, Wick MR, Folpe AL. Intercellular junctions in Ewing sarcoma/primitive neuroectodermal tumor: additional evidence of epithelial differentiation. Mod Pathol (2005) 18:1403-1410. doi:10.1038/modpathol.3800435
229. Burns WC, Twigg SM, Forbes JM, Pete J, Tikellis C, Thallas-Bonke V, Thomas MC, Cooper ME, Kantharidis P. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. J Am Soc Nephrol (2006) 17:2484-2494. doi:10.1681/ASN.2006050525
230. Voulgari A, Pintzas A. Epithelial-mesenchymal transition in cancer metastasis: Mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta-Rev Cancer (2009) 1796:75-90. doi:10.1016/j.bbcan.2009.03.002
231. Sarioglu AF, Aceto N, Kojic N, Donaldson MC, Zeinali M, Hamza B, Engstrom A, Zhu H, Sundaresan TK, Miyamoto DT, et al. A microfluidic device for label-free, physical capture of circulating tumor cell clusters. Nat Methods (2015) doi:10.1038/nmeth.3404