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Plasticity in Ovarian Cancer: The Molecular Underpinnings and Phenotypic Heterogeneity

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Journal of the Indian Institute of Science Aims and scope

Abstract

Cellular plasticity, by large, is the ability through which cells morph into new phenotypic identity by trading-off with the previous one. This phenomenon has been observed in the normal and tumor cells in a very similar fashion. Occurrence of cellular plasticity, in malignancies like epithelial ovarian carcinoma (EOC) are well known but highly debated in terms of origin of the tumor for the inherent heterogeneity across subtypes. EOC has been termed as a clinically challenging malady for its subversive nature against chemotherapy. The management of ovarian cancer is mostly hindered by relapse with recalcitrance towards primary chemotherapy regimen e.g. platinum–taxol combination. Also, late detection preceded by peritoneal metastasis poses another challenge to the treatment. Underlying both these aspects of the disease, tumor heterogeneity turns out as the most critical factor. In the light of heterogeneity that can be across patients (inter-tumoral) and/or within a tumor (intra-tumoral), ovarian carcinoma is a multifactorial ailment. The governing factors behind this heterogeneity are—diverse genetic landscape among subtypes of EOC; the presence of cancer stem cell (CSC) niche and inherent plasticity of the cancer cells themselves. Apart from the well-studied mechanisms of plasticity, there are several emerging molecular players like lncRNAs, Hippo pathway and also phenomena like dedifferentiation of non-CSC neoplastic cells ,and transdifferentiation of CSCs. Here, we present an overview of the current knowledge on the evolution of EOC through cellular plasticity with emphasis on the three major aspects namely, subtype-specific genetic diversity; ovarian CSC and cancer cell duality between epithelial and mesenchymal lineages.

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References

  1. Blau HM (2014) Sir John Gurdon: father of nuclear reprogramming. Differentiation 88:10–12. https://doi.org/10.1016/j.diff.2014.05.002

    Article  CAS  Google Scholar 

  2. Ge Y, Fuchs E (2018) Stretching the limits: from homeostasis to stem cell plasticity in wound healing and cancer. Nat Rev Genet 19:311–325. https://doi.org/10.1038/nrg.2018.9

    Article  CAS  Google Scholar 

  3. Truman AM, Tilly JL, Woods DC (2017) Ovarian regeneration: the potential for stem cell contribution in the postnatal ovary to sustained endocrine function. Mol Cell Endocrinol 445:74–84. https://doi.org/10.1016/j.mce.2016.10.012

    Article  CAS  Google Scholar 

  4. Vibert L, Daulny A, Jarriault S (2018) Wound healing, cellular regeneration and plasticity: the elegans way. Int J Dev Biol 62:491–505. https://doi.org/10.1387/ijdb.180123sj

    Article  CAS  Google Scholar 

  5. Carter LE, Cook DP, Vanderhyden BC (2019) In: Leung PCK, Adashi EY (eds) The ovary, 3rd edn. Academic Press, pp 529–545

  6. Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11:726–734. https://doi.org/10.1038/nrc3130

    Article  CAS  Google Scholar 

  7. Meacham CE, Morrison SJ (2013) Tumour heterogeneity and cancer cell plasticity. Nature 501:328–337. https://doi.org/10.1038/nature12624

    Article  CAS  Google Scholar 

  8. Anderson AR, Weaver AM, Cummings PT, Quaranta V (2006) Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. Cell 127:905–915. https://doi.org/10.1016/j.cell.2006.09.042

    Article  CAS  Google Scholar 

  9. Tian H et al (2011) A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478:255–259. https://doi.org/10.1038/nature10408

    Article  CAS  Google Scholar 

  10. Rompolas P, Mesa KR, Greco V (2013) Spatial organization within a niche as a determinant of stem-cell fate. Nature 502:513–518. https://doi.org/10.1038/nature12602

    Article  CAS  Google Scholar 

  11. Hoeck JD et al (2017) Stem cell plasticity enables hair regeneration following Lgr5(+) cell loss. Nat Cell Biol 19:666–676. https://doi.org/10.1038/ncb3535

    Article  CAS  Google Scholar 

  12. Merrell AJ, Stanger BZ (2016) Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style. Nat Rev Mol Cell Biol 17:413–425. https://doi.org/10.1038/nrm.2016.24

    Article  CAS  Google Scholar 

  13. Ito M et al (2007) Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature 447:316–320. https://doi.org/10.1038/nature05766

    Article  CAS  Google Scholar 

  14. Bray F et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492

    Article  Google Scholar 

  15. Wu SG et al (2019) Real-world impact of survival by period of diagnosis in epithelial ovarian cancer between 1990 and 2014. Front Oncol 9:639. https://doi.org/10.3389/fonc.2019.00639

    Article  Google Scholar 

  16. Auersperg N, Wong AST, Choi K-C, Kang SK, Leung PCK (2001) Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr Rev 22:255–288. https://doi.org/10.1210/edrv.22.2.0422

    Article  CAS  Google Scholar 

  17. Ahmed N, Thompson EW, Quinn MA (2007) Epithelial–mesenchymal interconversions in normal ovarian surface epithelium and ovarian carcinomas: an exception to the norm. J Cell Physiol 213:581–588. https://doi.org/10.1002/jcp.21240

    Article  CAS  Google Scholar 

  18. Levanon K, Crum C, Drapkin R (2008) New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol 26:5284–5293. https://doi.org/10.1200/JCO.2008.18.1107

    Article  Google Scholar 

  19. Salvador S et al (2009) The fallopian tube: primary site of most pelvic high-grade serous carcinomas. Int J Gynecol Cancer 19:58–64. https://doi.org/10.1111/IGC.0b013e318199009c

    Article  Google Scholar 

  20. Carter LE, Cook DP, Vanderhyden BC (2019) Phenotypic plasticity and the origins and progression of ovarian cancer. Ovary. https://doi.org/10.1016/b978-0-12-813209-8.00033-9

    Article  Google Scholar 

  21. Auersperg N (2011) The origin of ovarian carcinomas: a unifying hypothesis. Int J Gynecol Pathol 30:12–21. https://doi.org/10.1097/PGP.0b013e3181f45f3e

    Article  Google Scholar 

  22. Erickson BK, Conner MG, Landen CN Jr (2013) The role of the fallopian tube in the origin of ovarian cancer. Am J Obstet Gynecol 209:409–414. https://doi.org/10.1016/j.ajog.2013.04.019

    Article  Google Scholar 

  23. Jarboe EA et al (2009) Tubal and ovarian pathways to pelvic epithelial cancer: a pathological perspective. Histopathology 55:619. https://doi.org/10.1111/j.1365-2559.2009.03408.x

    Article  Google Scholar 

  24. Chen VW et al (2003) Pathology and classification of ovarian tumors. Cancer 97:2631–2642. https://doi.org/10.1002/cncr.11345

    Article  Google Scholar 

  25. Kurman RJ, Shih I-M (2010) The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 34:433–443. https://doi.org/10.1097/PAS.0b013e3181cf3d79

    Article  Google Scholar 

  26. The Cancer Genome Atlas Research, N et al (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474:609. doi: 10.1038/nature10166. https://www.nature.com/articles/nature10166#supplementary-information

  27. Berns EMJJ, Bowtell DD (2012) The changing view of high-grade serous ovarian cancer. Cancer Res 72:2701–2704. https://doi.org/10.1158/0008-5472.can-11-3911

    Article  CAS  Google Scholar 

  28. Cancer Genome Atlas Research, N (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474:609–615. https://doi.org/10.1038/nature10166

    Article  CAS  Google Scholar 

  29. Verhaak RG et al (2013) Prognostically relevant gene signatures of high-grade serous ovarian carcinoma. J Clin Invest 123:517–525. https://doi.org/10.1172/JCI65833

    Article  CAS  Google Scholar 

  30. Tothill RW et al (2008) Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res 14:5198–5208. https://doi.org/10.1158/1078-0432.CCR-08-0196

    Article  CAS  Google Scholar 

  31. Ince TA et al (2015) Characterization of twenty-five ovarian tumour cell lines that phenocopy primary tumours. Nat Commun 6:7419. https://doi.org/10.1038/ncomms8419

    Article  CAS  Google Scholar 

  32. Hirst J, Crow J, Godwin A (2018) Ovarian cancer genetics: subtypes and risk factors. Ovarian Cancer Pathog Treat. https://doi.org/10.5772/intechopen.72705

    Article  Google Scholar 

  33. Smith Sehdev AE, Sehdev PS, Kurman RJ (2003) Noninvasive and invasive micropapillary (low-grade) serous carcinoma of the ovary: a clinicopathologic analysis of 135 cases. Am J Surg Pathol 27:725–736. https://doi.org/10.1097/00000478-200306000-00003

    Article  Google Scholar 

  34. Malpica A et al (2004) Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol 28:496–504. https://doi.org/10.1097/00000478-200404000-00009

    Article  Google Scholar 

  35. Singer G, Shih Ie M, Truskinovsky A, Umudum H, Kurman RJ (2003) Mutational analysis of K-ras segregates ovarian serous carcinomas into two types: invasive MPSC (low-grade tumor) and conventional serous carcinoma (high-grade tumor). Int J Gynecol Pathol 22:37–41. https://doi.org/10.1097/00004347-200301000-00009

    Article  Google Scholar 

  36. Vang R, Shih Ie M, Kurman RJ (2009) Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Adv Anat Pathol 16:267–282. https://doi.org/10.1097/PAP.0b013e3181b4fffa

    Article  Google Scholar 

  37. Parker RL, Clement PB, Chercover DJ, Sornarajah T, Gilks CB (2004) Early recurrence of ovarian serous borderline tumor as high-grade carcinoma: a report of two cases. Int J Gynecol Pathol 23:265–272. https://doi.org/10.1097/01.pgp.0000130049.19643.f6

    Article  Google Scholar 

  38. Kurman RJ, Craig JM (1972) Endometrioid and clear cell carcinoma of the ovary. Cancer 29:1653–1664. https://doi.org/10.1002/1097-0142(197206)29:6%3c1653:aid-cncr2820290633%3e3.0.co;2-e

    Article  CAS  Google Scholar 

  39. Terada T (2012) Endometrioid adenocarcinoma of the ovary arising in atypical endometriosis. Int J Clin Exp Pathol 5:924–927

    Google Scholar 

  40. Xy J, Wp Z, Mf W (2017) The clinical characteristics and prognosis of ovarian endometrioid carcinoma. Integr Cancer Sci Ther. https://doi.org/10.15761/icst.1000239

    Article  Google Scholar 

  41. Hollis RL, Gourley C (2016) Genetic and molecular changes in ovarian cancer. Cancer Biol Med 13:236–247. https://doi.org/10.20892/j.issn.2095-3941.2016.0024

    Article  CAS  Google Scholar 

  42. Bell DA (2005) Origins and molecular pathology of ovarian cancer. Mod Pathol 18:S19–S32. https://doi.org/10.1038/modpathol.3800306

    Article  CAS  Google Scholar 

  43. Gilks CB (2010) Molecular abnormalities in ovarian cancer subtypes other than high-grade serous carcinoma. J Oncol 740968–740968:2010. https://doi.org/10.1155/2010/740968

    Article  CAS  Google Scholar 

  44. Cheasley D et al (2019) The molecular origin and taxonomy of mucinous ovarian carcinoma. Nat Commun 10:3935–3935. https://doi.org/10.1038/s41467-019-11862-x

    Article  CAS  Google Scholar 

  45. Lupia M, Cavallaro U (2017) Ovarian cancer stem cells: still an elusive entity? Mol Cancer 16:64

    Article  Google Scholar 

  46. Abdullah LN, Chow EK-H (2013) Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2:3

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  48. Bapat SA, Mali AM, Koppikar CB, Kurrey NK (2005) Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Can Res 65:3025–3029

    Article  CAS  Google Scholar 

  49. Alvero AB et al (2009) Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle 8:158–166. https://doi.org/10.4161/cc.8.1.7533

    Article  CAS  Google Scholar 

  50. Hu L, McArthur C, Jaffe RB (2010) Ovarian cancer stem-like side-population cells are tumourigenic and chemoresistant. Br J Cancer 102:1276–1283. https://doi.org/10.1038/sj.bjc.6605626

    Article  CAS  Google Scholar 

  51. Boesch M, Wolf D, Sopper S (2016) Optimized stem cell detection using the dyecycle-triggered side population phenotype. Stem Cells Int 2016:1652389. https://doi.org/10.1155/2016/1652389

    Article  CAS  Google Scholar 

  52. Landen CN et al (2010) Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer. Mol Cancer Ther 9:3186–3199

    Article  CAS  Google Scholar 

  53. Zhang S et al (2008) Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res 68:4311–4320. https://doi.org/10.1158/0008-5472.CAN-08-0364

    Article  CAS  Google Scholar 

  54. Slomiany MG et al (2009) Inhibition of functional hyaluronan-CD44 interactions in CD133-positive primary human ovarian carcinoma cells by small hyaluronan oligosaccharides. Clin Cancer Res 15:7593–7601. https://doi.org/10.1158/1078-0432.CCR-09-2317

    Article  CAS  Google Scholar 

  55. Latifi A et al (2012) Isolation and characterization of tumor cells from the ascites of ovarian cancer patients: molecular phenotype of chemoresistant ovarian tumors. PLoS ONE 7:e46858. https://doi.org/10.1371/journal.pone.0046858

    Article  CAS  Google Scholar 

  56. Zhang S et al (2014) Ovarian cancer stem cells express ROR1, which can be targeted for anti-cancer-stem-cell therapy. Proc Natl Acad Sci USA 111:17266–17271. https://doi.org/10.1073/pnas.1419599111

    Article  CAS  Google Scholar 

  57. Ruan Z, Yang X, Cheng W (2019) OCT4 accelerates tumorigenesis through activating JAK/STAT signaling in ovarian cancer side population cells. Cancer Manag Res 11:389–399. https://doi.org/10.2147/CMAR.S180418

    Article  CAS  Google Scholar 

  58. Wen Y, Hou Y, Huang Z, Cai J, Wang Z (2017) SOX2 is required to maintain cancer stem cells in ovarian cancer. Cancer Sci 108:719–731. https://doi.org/10.1111/cas.13186

    Article  CAS  Google Scholar 

  59. Pan Y et al (2010) Nanog is highly expressed in ovarian serous cystadenocarcinoma and correlated with clinical stage and pathological grade. Pathobiology J Immunopathol Mol Cell Biol 77:283–288. https://doi.org/10.1159/000320866

    Article  Google Scholar 

  60. Kobayashi Y et al (2011) Side population is increased in paclitaxel-resistant ovarian cancer cell lines regardless of resistance to cisplatin. Gynecol Oncol 121:390–394. https://doi.org/10.1016/j.ygyno.2010.12.366

    Article  CAS  Google Scholar 

  61. Wang A, Chen L, Li C, Zhu Y (2015) Heterogeneity in cancer stem cells. Cancer Lett 357:63–68. https://doi.org/10.1016/j.canlet.2014.11.040

    Article  CAS  Google Scholar 

  62. Tang DG (2012) Understanding cancer stem cell heterogeneity and plasticity. Cell Res 22:457–472. https://doi.org/10.1038/cr.2012.13

    Article  CAS  Google Scholar 

  63. Singh RK, Dhadve A, Sakpal A, De A, Ray P (2016) An active IGF-1R-AKT signaling imparts functional heterogeneity in ovarian CSC population. Sci Rep 6:36612

    Article  CAS  Google Scholar 

  64. Cabrera MC, Hollingsworth RE, Hurt EM (2015) Cancer stem cell plasticity and tumor hierarchy. World J Stem Cells 7:27–36. https://doi.org/10.4252/wjsc.v7.i1.27

    Article  Google Scholar 

  65. Boesch M et al (1866) Heterogeneity of cancer stem cells: rationale for targeting the stem cell niche. Biochem Biophys Acta 276–289:2016. https://doi.org/10.1016/j.bbcan.2016.10.003

    Article  CAS  Google Scholar 

  66. Abelson S et al (2012) Intratumoral heterogeneity in the self-renewal and tumorigenic differentiation of ovarian cancer. Stem Cells 30:415–424

    Article  CAS  Google Scholar 

  67. Cui T et al (2018) DDB2 represses ovarian cancer cell dedifferentiation by suppressing ALDH1A1. Cell Death Dis 9:561

    Article  Google Scholar 

  68. Liu KC et al (2013) Ovarian cancer stem-like cells show induced translineage-differentiation capacity and are suppressed by alkaline phosphatase inhibitor. Oncotarget 4:2366–2382. https://doi.org/10.18632/oncotarget.1424

    Article  Google Scholar 

  69. Ramakrishnan M, Mathur SR, Mukhopadhyay A (2013) Fusion-derived epithelial cancer cells express hematopoietic markers and contribute to stem cell and migratory phenotype in ovarian carcinoma. Cancer Res 73:5360–5370. https://doi.org/10.1158/0008-5472.CAN-13-0896

    Article  CAS  Google Scholar 

  70. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428. https://doi.org/10.1172/JCI39104

    Article  CAS  Google Scholar 

  71. Gupta S, Maitra A (2016) EMT: matter of life or death? Cell 164:840–842. https://doi.org/10.1016/j.cell.2016.02.024

    Article  CAS  Google Scholar 

  72. Klymenko Y, Kim O, Stack MS (2017) Complex determinants of epithelial: mesenchymal phenotypic plasticity in ovarian cancer. Cancers (Basel). https://doi.org/10.3390/cancers9080104

    Article  Google Scholar 

  73. Jackstadt R et al (2019) Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis. Cancer Cell 36:319–336 e317. https://doi.org/10.1016/j.ccell.2019.08.003

    Article  CAS  Google Scholar 

  74. Yao D, Dai C, Peng S (2011) Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res 9:1608–1620. https://doi.org/10.1158/1541-7786.MCR-10-0568

    Article  CAS  Google Scholar 

  75. Pastushenko I et al (2018) Identification of the tumour transition states occurring during EMT. Nature 556:463–468. https://doi.org/10.1038/s41586-018-0040-3

    Article  CAS  Google Scholar 

  76. Guadamillas MC, Cerezo A, Del Pozo MA (2011) Overcoming anoikis–pathways to anchorage-independent growth in cancer. J Cell Sci 124:3189–3197. https://doi.org/10.1242/jcs.072165

    Article  CAS  Google Scholar 

  77. Ahmed N, Abubaker K, Findlay J, Quinn M (2010) Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer. Curr Cancer Drug Targets 10:268–278. https://doi.org/10.2174/156800910791190175

    Article  CAS  Google Scholar 

  78. Loret N, Denys H, Tummers P, Berx G (2019) The role of epithelial-to-mesenchymal plasticity in ovarian cancer progression and therapy resistance. Cancers (Basel). https://doi.org/10.3390/cancers11060838

    Article  Google Scholar 

  79. Alwosaibai K et al (2017) PAX2 maintains the differentiation of mouse oviductal epithelium and inhibits the transition to a stem cell-like state. Oncotarget 8:76881–76897. https://doi.org/10.18632/oncotarget.20173

    Article  Google Scholar 

  80. Dean M, Davis DA, Burdette JE (2017) Activin A stimulates migration of the fallopian tube epithelium, an origin of high-grade serous ovarian cancer, through non-canonical signaling. Cancer Lett 391:114–124. https://doi.org/10.1016/j.canlet.2017.01.011

    Article  CAS  Google Scholar 

  81. Newsted D et al (2019) Blockade of TGF-beta signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models. Oncoimmunology 8:e1539613. https://doi.org/10.1080/2162402X.2018.1539613

    Article  Google Scholar 

  82. Tan DSP, Agarwal R, Kaye SB (2006) Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet Oncol 7:925–934. https://doi.org/10.1016/S1470-2045(06)70939-1

    Article  Google Scholar 

  83. Pradeep S et al (2014) Hematogenous metastasis of ovarian cancer: rethinking mode of spread. Cancer Cell 26:77–91. https://doi.org/10.1016/j.ccr.2014.05.002

    Article  CAS  Google Scholar 

  84. Al Habyan S, Kalos C, Szymborski J, McCaffrey L (2018) Multicellular detachment generates metastatic spheroids during intra-abdominal dissemination in epithelial ovarian cancer. Oncogene 37:5127–5135. https://doi.org/10.1038/s41388-018-0317-x

    Article  CAS  Google Scholar 

  85. Li G et al (2018) Frizzled7 promotes epithelial-to-mesenchymal transition and stemness via activating canonical Wnt/beta-catenin pathway in gastric cancer. Int J Biol Sci 14:280–293. https://doi.org/10.7150/ijbs.23756

    Article  CAS  Google Scholar 

  86. Chen Y et al (2019) WFDC2 contributes to epithelial-mesenchymal transition (EMT) by activating AKT signaling pathway and regulating MMP-2 expression. Cancer Manag Res 11:2415–2424. https://doi.org/10.2147/CMAR.S192950

    Article  CAS  Google Scholar 

  87. Westermann AM et al (1998) Malignant effusions contain lysophosphatidic acid (LPA)-like activity. Ann Oncol 9:437–442. https://doi.org/10.1023/a:1008217129273

    Article  CAS  Google Scholar 

  88. Sutphen R et al (2004) Lysophospholipids are potential biomarkers of ovarian cancer. Cancer Epidemiol Biomark Prev 13:1185–1191

    CAS  Google Scholar 

  89. Sadlecki P et al (2019) Expression of zinc finger transcription factors (ZNF143 and ZNF281) in serous borderline ovarian tumors and low-grade ovarian cancers. J Ovarian Res 12:23. https://doi.org/10.1186/s13048-019-0501-9

    Article  Google Scholar 

  90. Sadlecki P, Jozwicki J, Antosik P, Grabiec M (2018) Expression of selected epithelial-mesenchymal transition transcription factors in serous borderline ovarian tumors and type I ovarian cancers. Tumour Biol 40:1010428318784807. https://doi.org/10.1177/1010428318784807

    Article  CAS  Google Scholar 

  91. Cheng JC, Auersperg N, Leung PC (2011) Inhibition of p53 induces invasion of serous borderline ovarian tumor cells by accentuating PI3K/Akt-mediated suppression of E-cadherin. Oncogene 30:1020–1031. https://doi.org/10.1038/onc.2010.486

    Article  CAS  Google Scholar 

  92. Moffitt L, Karimnia N, Stephens A, Bilandzic M (2019) Therapeutic targeting of collective invasion in ovarian cancer. Int J Mol Sci. https://doi.org/10.3390/ijms20061466

    Article  Google Scholar 

  93. Qian B-Z et al (2015) FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J Exp Med 212:1433–1448. https://doi.org/10.1084/jem.20141555

    Article  CAS  Google Scholar 

  94. Terabe M et al (2003) Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med 198:1741–1752. https://doi.org/10.1084/jem.20022227

    Article  CAS  Google Scholar 

  95. Vander Griend DJ et al (2005) Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7. Can Res 65:10984. https://doi.org/10.1158/0008-5472.CAN-05-2382

    Article  CAS  Google Scholar 

  96. Kurrey NK et al (2009) Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27:2059–2068. https://doi.org/10.1002/stem.154

    Article  CAS  Google Scholar 

  97. He P, Qiu K, Jia Y (2018) Modeling of mesenchymal hybrid epithelial state and phenotypic transitions in EMT and MET processes of cancer cells. Sci Rep 8:14323. https://doi.org/10.1038/s41598-018-32737-z

    Article  CAS  Google Scholar 

  98. Strauss R et al (2011) Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity. PLoS ONE 6:e16186. https://doi.org/10.1371/journal.pone.0016186

    Article  CAS  Google Scholar 

  99. Jolly MK et al (2018) Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer. APL Bioeng 2:031908–031908. https://doi.org/10.1063/1.5024874

    Article  CAS  Google Scholar 

  100. Bracken CP et al (2008) A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res 68:7846–7854. https://doi.org/10.1158/0008-5472.can-08-1942

    Article  CAS  Google Scholar 

  101. Siemens H et al (2011) miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle 10:4256–4271. https://doi.org/10.4161/cc.10.24.18552

    Article  CAS  Google Scholar 

  102. Hu Z et al (2019) The repertoire of serous ovarian cancer non-genetic heterogeneity revealed by single-cell sequencing of normal fallopian tube epithelial cells. bioRxiv 672626. doi:10.1101/672626

  103. Varankar SS et al (2019) Functional balance between Tcf21–Slug defines cellular plasticity and migratory modalities in high grade serous ovarian cancer cell lines. Carcinogenesis. https://doi.org/10.1093/carcin/bgz119

    Article  Google Scholar 

  104. Jolly MK, Kulkarni P, Weninger K, Orban J, Levine H (2018) Phenotypic plasticity, bet-hedging, and androgen independence in prostate cancer: role of non-genetic heterogeneity. Front Oncol 8:50–50. https://doi.org/10.3389/fonc.2018.00050

    Article  Google Scholar 

  105. Moyed HS, Bertrand KP (1983) hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol 155:768–775

    Article  CAS  Google Scholar 

  106. Sharma SV et al (2010) A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141:69–80. https://doi.org/10.1016/j.cell.2010.02.027

    Article  CAS  Google Scholar 

  107. Beaumont HJE, Gallie J, Kost C, Ferguson GC, Rainey PB (2009) Experimental evolution of bet hedging. Nature 462:90–93. https://doi.org/10.1038/nature08504

    Article  CAS  Google Scholar 

  108. Yang Q et al (2018) Analysis of LncRNA expression in cell differentiation. RNA Biol 15:413–422. https://doi.org/10.1080/15476286.2018.1441665

    Article  Google Scholar 

  109. Li C, Hu G, Wei B, Wang L, Liu N (2019) lncRNA LINC01494 promotes proliferation, migration and invasion in glioma through miR-122-5p/CCNG1 axis. Onco Targets Ther 12:7655–7662. https://doi.org/10.2147/OTT.S213345

    Article  CAS  Google Scholar 

  110. Rossi MN, Antonangeli F (2014) LncRNAs: new players in apoptosis control. Int J Cell Biol 2014:473857. https://doi.org/10.1155/2014/473857

    Article  CAS  Google Scholar 

  111. Zhou M et al (2016) Comprehensive analysis of lncRNA expression profiles reveals a novel lncRNA signature to discriminate nonequivalent outcomes in patients with ovarian cancer. Oncotarget 7:32433–32448. https://doi.org/10.18632/oncotarget.8653

    Article  Google Scholar 

  112. Xia B et al (2017) Long non-coding RNA ZFAS1 interacts with miR-150-5p to regulate Sp1 expression and ovarian cancer cell malignancy. Oncotarget 8:19534–19546. https://doi.org/10.18632/oncotarget.14663

    Article  Google Scholar 

  113. Qiu JJ et al (2014) Overexpression of long non-coding RNA HOTAIR predicts poor patient prognosis and promotes tumor metastasis in epithelial ovarian cancer. Gynecol Oncol 134:121–128. https://doi.org/10.1016/j.ygyno.2014.03.556

    Article  CAS  Google Scholar 

  114. Richards EJ et al (2015) Long non-coding RNAs (LncRNA) regulated by transforming growth factor (TGF) beta: LncRNA-hit-mediated TGFbeta-induced epithelial to mesenchymal transition in mammary epithelia. J Biol Chem 290:6857–6867. https://doi.org/10.1074/jbc.M114.610915

    Article  CAS  Google Scholar 

  115. Xia Y et al (2014) YAP promotes ovarian cancer cell tumorigenesis and is indicative of a poor prognosis for ovarian cancer patients. PLoS ONE 9:e91770. https://doi.org/10.1371/journal.pone.0091770

    Article  CAS  Google Scholar 

  116. Hall CA et al (2010) Hippo pathway effector Yap is an ovarian cancer oncogene. Cancer Res 70:8517–8525. https://doi.org/10.1158/0008-5472.CAN-10-1242

    Article  CAS  Google Scholar 

  117. Wu X et al (2018) Sialyltransferase ST3GAL1 promotes cell migration, invasion, and TGF-beta1-induced EMT and confers paclitaxel resistance in ovarian cancer. Cell Death Dis 9:1102. https://doi.org/10.1038/s41419-018-1101-0

    Article  CAS  Google Scholar 

  118. Zhang M et al (2019) Pyruvate dehydrogenase kinase 1 contributes to cisplatin resistance of ovarian cancer through EGFR activation. J Cell Physiol 234:6361–6370. https://doi.org/10.1002/jcp.27369

    Article  CAS  Google Scholar 

  119. Tung SL et al (2017) miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERK pathway. Oncogenesis 6:e326. https://doi.org/10.1038/oncsis.2017.25

    Article  CAS  Google Scholar 

  120. Zaytseva YY et al (2012) Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res 72:1504–1517. https://doi.org/10.1158/0008-5472.CAN-11-4057

    Article  CAS  Google Scholar 

  121. Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7:763–777. https://doi.org/10.1038/nrc2222

    Article  CAS  Google Scholar 

  122. Furuta E, Okuda H, Kobayashi A, Watabe K (1805) Metabolic genes in cancer: their roles in tumor progression and clinical implications. Biochim Biophys Acta 141–152:2010. https://doi.org/10.1016/j.bbcan.2010.01.005

    Article  CAS  Google Scholar 

  123. Jiang L et al (2014) Up-regulated FASN expression promotes transcoelomic metastasis of ovarian cancer cell through epithelial-mesenchymal transition. Int J Mol Sci 15:11539–11554. https://doi.org/10.3390/ijms150711539

    Article  CAS  Google Scholar 

  124. Qin G et al (2015) Palbociclib inhibits epithelial-mesenchymal transition and metastasis in breast cancer via c-Jun/COX-2 signaling pathway. Oncotarget 6:41794–41808. https://doi.org/10.18632/oncotarget.5993

    Article  Google Scholar 

  125. Wang YP, Wang QY, Li CH, Li XW (2018) COX-2 inhibition by celecoxib in epithelial ovarian cancer attenuates E-cadherin suppression through reduced Snail nuclear translocation. Chem Biol Interact 292:24–29. https://doi.org/10.1016/j.cbi.2018.06.020

    Article  CAS  Google Scholar 

  126. Voth W, Jakob U (2017) Stress-activated chaperones: a first line of defense. Trends Biochem Sci 42:899–913. https://doi.org/10.1016/j.tibs.2017.08.006

    Article  CAS  Google Scholar 

  127. Amoroso MR et al (2016) TRAP1 downregulation in human ovarian cancer enhances invasion and epithelial-mesenchymal transition. Cell Death Dis 7:e2522. https://doi.org/10.1038/cddis.2016.400

    Article  CAS  Google Scholar 

  128. Na Y et al (2016) Stress chaperone mortalin contributes to epithelial-to-mesenchymal transition and cancer metastasis. Cancer Res 76:2754–2765. https://doi.org/10.1158/0008-5472.can-15-2704

    Article  CAS  Google Scholar 

  129. Chen SN et al (2019) MicroRNA in ovarian cancer: biology, pathogenesis, and therapeutic opportunities. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph16091510

    Article  Google Scholar 

  130. Nam EJ et al (2008) MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 14:2690–2695. https://doi.org/10.1158/1078-0432.CCR-07-1731

    Article  CAS  Google Scholar 

  131. Park SM, Gaur AB, Lengyel E, Peter ME (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22:894–907. https://doi.org/10.1101/gad.1640608

    Article  CAS  Google Scholar 

  132. Gregory PA et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:593–601. https://doi.org/10.1038/ncb1722

    Article  CAS  Google Scholar 

  133. Lee Y et al (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415–419. https://doi.org/10.1038/nature01957

    Article  CAS  Google Scholar 

  134. Lin Y, Xu T, Zhou S, Cui M (2017) MicroRNA-363 inhibits ovarian cancer progression by inhibiting NOB1. Oncotarget 8:101649–101658. https://doi.org/10.18632/oncotarget.21417

    Article  Google Scholar 

  135. Mohamed Z et al (2018) miR-363 confers taxane resistance in ovarian cancer by targeting the Hippo pathway member, LATS2. Oncotarget 9:30053–30065. https://doi.org/10.18632/oncotarget.25698

    Article  Google Scholar 

  136. Zhu X et al (2016) miR-186 regulation of Twist1 and ovarian cancer sensitivity to cisplatin. Oncogene 35:323–332. https://doi.org/10.1038/onc.2015.84

    Article  CAS  Google Scholar 

  137. Dong S et al (2019) HOXD-AS1 promotes the epithelial to mesenchymal transition of ovarian cancer cells by regulating miR-186-5p and PIK3R3. J Exp Clin Cancer Res 38:110. https://doi.org/10.1186/s13046-019-1103-5

    Article  Google Scholar 

  138. Liu Y et al (2017) MicroRNA-20a contributes to cisplatin-resistance and migration of OVCAR3 ovarian cancer cell line. Oncol Lett 14:1780–1786. https://doi.org/10.3892/ol.2017.6348

    Article  CAS  Google Scholar 

  139. Wang Y, Kim S, Kim IM (2014) Regulation of metastasis by microRNAs in ovarian cancer. Front Oncol 4:143. https://doi.org/10.3389/fonc.2014.00143

    Article  Google Scholar 

  140. Li L et al (2016) MiR-181a upregulation is associated with epithelial-to-mesenchymal transition (EMT) and multidrug resistance (MDR) of ovarian cancer cells. Eur Rev Med Pharmacol Sci 20:2004–2010

    CAS  Google Scholar 

  141. Au Yeung CL et al (2016) Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun 7:11150. https://doi.org/10.1038/ncomms11150

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Imaging Cell Signalling and Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India

    Souvik Mukherjee, Pratham Phadte, Megha Mehrotra & Pritha Ray

  2. Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India

    Souvik Mukherjee, Pratham Phadte, Megha Mehrotra & Pritha Ray

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All authors have participated in concept design and preparation of the manuscript. PR, PP, MM and SM have contributed in literature mining and data interpretation. PR has also critically analysed the manuscript and all authors have agreed upon the submitted version of the manuscript.

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Mukherjee, S., Phadte, P., Mehrotra, M. et al. Plasticity in Ovarian Cancer: The Molecular Underpinnings and Phenotypic Heterogeneity. J Indian Inst Sci 100, 537–553 (2020). https://doi.org/10.1007/s41745-020-00174-5

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