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36. Meacham CE, Morrison SJ (2013) Tumour
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501:328–337.
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37. Lapidot T, Sirard C, Vormoor J et al (1994) A
cell initiating human acute myeloid leukaemia
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367645a0
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et al (2003) Prospective identification of
tumorigenic breast cancer cells. Proc Natl
Acad Sci 100:3983–3988. https://doi.org/
10.1073/pnas.0530291100
39. O’Brien CA, Pollett A, Gallinger S, Dick JE
(2007) A human colon cancer cell capable of
initiating tumour growth in immunodeficient
mice. Nature 445:106–110. https://doi.org/
10.1038/nature05372
40. Ricci-Vitiani L, Lombardi DG, Pilozzi E et al
(2007) Identification and expansion of human
colon-cancer-initiating
cells.
Nature
445:111–115.
https://doi.org/10.1038/
nature05384
41. Singh SK, Hawkins C, Clarke ID et al (2004)
Identification of human brain tumour initiating cells. Nature 432:396–401. https://doi.
org/10.1038/nature03128
42. Collins AT, Berry PA, Hyde C et al (2005)
Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res
65:10946–10951. https://doi.org/10.1158/
0008-5472.CAN-05-2018
43. Lehmann BD, Bauer JA, Chen X et al (2011)
Identification of human triple-negative breast
cancer subtypes and preclinical models for
selection of targeted therapies. J Clin Invest
121:2750–2767. https://doi.org/10.1172/
JCI45014
44. Calbo J, van Montfort E, Proost N et al (2011)
A functional role for tumor cell heterogeneity
in a mouse model of small cell lung cancer.
Cancer Cell 19:244–256. https://doi.org/10.
1016/j.ccr.2010.12.021
45. Stanta G, Bonin S (2018) Overview on clinical
relevance of intra-tumor heterogeneity. Front
Med 5:85. https://doi.org/10.3389/fmed.
2018.00085
46. Hong D, Fritz AJ, Zaidi SK et al (2018)
Epithelial-to-mesenchymal transition and cancer stem cells contribute to breast cancer heterogeneity. J Cell Physiol 233:9136–9144.
https://doi.org/10.1002/jcp.26847
47. Kim JE, Leung EY, Baguley BC, Finlay GJ
(2013) Heterogeneity of expression of epithelial–mesenchymal transition markers in melanocytes and melanoma cell lines. Front Genet
4:97. https://doi.org/10.3389/fgene.2013.
00097
48. Pereira L, Mariadason JM, Hannan RD, Dhillon AS (2015) Implications of epithelial–mesenchymal plasticity for heterogeneity in
colorectal cancer. Front Oncol 5:13. https://
doi.org/10.3389/fonc.2015.00013
49. Stylianou N, Lehman ML, Wang C et al (2018)
A molecular portrait of epithelial–mesenchymal
Mathematical Modelling of EMT
411
org/10.1002/wsbm.1273
26. Zhang J, Tian X-J, Chen Y-J et al (2018) Pathway crosstalk enables cells to interpret TGF-β
duration. NPJ Syst Biol Appl 4:18. https://doi.
org/10.1038/s41540-018-0060-5
27. Blagoev KB, Shukla K, Levine H (2013) We
need theoretical physics approaches to study
living systems. Phys Biol 10:040201. https://
doi.org/10.1088/1478-3975/10/4/
040201
28. Zhang J, Tian X-J, Zhang H et al (2014)
TGF-β–induced
epithelial-to-mesenchymal
transition proceeds through stepwise activation
of multiple feedback loops. Sci Signal 7:ra91.
https://doi.org/10.1126/scisignal.2005304
29. Bustin SA, Huggett JF (2017) Reproducibility
of biomedical research – the importance of
editorial vigilance. Biomol Detect Quantif
11:1–3.
https://doi.org/10.1016/j.bdq.
2017.01.002
30. Fu Y, Glaros T, Zhu M et al (2012) Network
topologies and dynamics leading to endotoxin
tolerance and priming in innate immune cells.
PLoS Comput Biol 8:1–14. https://doi.org/
10.1371/journal.pcbi.1002526
31. Wang P, Song C, Zhang H et al (2014) Epigenetic state network approach for describing cell
phenotypic transitions. Interface Focus
4:20130068. https://doi.org/10.1098/rsfs.
2013.0068
32. Harris LA, Hogg JS, Tapia J-J et al (2016)
BioNetGen 2.2: advances in rule-based modeling. Bioinformatics 32:3366–3368. https://
doi.org/10.1093/bioinformatics/btw469
33. Box GEP (1976) Science and statistics. J Am
Stat Assoc 71:791–799. https://doi.org/10.
1080/01621459.1976.10480949
34. Jolly MK, Tripathi SC, Jia D et al (2016) Stability of the hybrid epithelial/mesenchymal
phenotype. Oncotarget 7:27067–27084.
https://doi.org/10.18632/oncotarget.8166
35. Jolly MK, Preca B-T, Tripathi SC et al (2018)
Interconnected feedback loops among ESRP1,
HAS2, and CD44 regulate epithelialmesenchymal plasticity in cancer. APL Bioeng
2:031908.
https://doi.org/10.1063/1.
5024874
36. Meacham CE, Morrison SJ (2013) Tumour
heterogeneity and cancer cell plasticity. Nature
501:328–337.
https://doi.org/10.1038/
nature12624
37. Lapidot T, Sirard C, Vormoor J et al (1994) A
cell initiating human acute myeloid leukaemia
after transplantation into SCID mice. Nature
367:645–648.
https://doi.org/10.1038/
367645a0
38. Al-Hajj M, Wicha MS, Benito-Hernandez A
et al (2003) Prospective identification of
tumorigenic breast cancer cells. Proc Natl
Acad Sci 100:3983–3988. https://doi.org/
10.1073/pnas.0530291100
39. O’Brien CA, Pollett A, Gallinger S, Dick JE
(2007) A human colon cancer cell capable of
initiating tumour growth in immunodeficient
mice. Nature 445:106–110. https://doi.org/
10.1038/nature05372
40. Ricci-Vitiani L, Lombardi DG, Pilozzi E et al
(2007) Identification and expansion of human
colon-cancer-initiating
cells.
Nature
445:111–115.
https://doi.org/10.1038/
nature05384
41. Singh SK, Hawkins C, Clarke ID et al (2004)
Identification of human brain tumour initiating cells. Nature 432:396–401. https://doi.
org/10.1038/nature03128
42. Collins AT, Berry PA, Hyde C et al (2005)
Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res
65:10946–10951. https://doi.org/10.1158/
0008-5472.CAN-05-2018
43. Lehmann BD, Bauer JA, Chen X et al (2011)
Identification of human triple-negative breast
cancer subtypes and preclinical models for
selection of targeted therapies. J Clin Invest
121:2750–2767. https://doi.org/10.1172/
JCI45014
44. Calbo J, van Montfort E, Proost N et al (2011)
A functional role for tumor cell heterogeneity
in a mouse model of small cell lung cancer.
Cancer Cell 19:244–256. https://doi.org/10.
1016/j.ccr.2010.12.021
45. Stanta G, Bonin S (2018) Overview on clinical
relevance of intra-tumor heterogeneity. Front
Med 5:85. https://doi.org/10.3389/fmed.
2018.00085
46. Hong D, Fritz AJ, Zaidi SK et al (2018)
Epithelial-to-mesenchymal transition and cancer stem cells contribute to breast cancer heterogeneity. J Cell Physiol 233:9136–9144.
https://doi.org/10.1002/jcp.26847
47. Kim JE, Leung EY, Baguley BC, Finlay GJ
(2013) Heterogeneity of expression of epithelial–mesenchymal transition markers in melanocytes and melanoma cell lines. Front Genet
4:97. https://doi.org/10.3389/fgene.2013.
00097
48. Pereira L, Mariadason JM, Hannan RD, Dhillon AS (2015) Implications of epithelial–mesenchymal plasticity for heterogeneity in
colorectal cancer. Front Oncol 5:13. https://
doi.org/10.3389/fonc.2015.00013
49. Stylianou N, Lehman ML, Wang C et al (2018)
A molecular portrait of epithelial–mesenchymal
Mathematical Modelling of EMT
411