Clinical impact of epithelial–mesenchymal transition for cancer therapy

Abstract

The epithelial-mesenchymal transition (EMT) represents a pivotal frontier in oncology, playing a central role in the metastatic cascade of cancer—a leading global health challenge. This comprehensive review delves into the complexities of EMT, a process where cancer cells gain exceptional mobility, facilitating their invasion into distant organs and the establishment of secondary malignancies. We thoroughly examine the myriad of factors influencing EMT, encompassing transcription factors, signalling pathways, metabolic alterations, microRNAs, long non-coding RNAs, epigenetic changes, exosomal interactions and the intricate dynamics of the tumour microenvironment. Particularly, the review emphasises the advanced stages of EMT, crucial for the development of highly aggressive cancer phenotypes. During this phase, cancer cells penetrate the vascular barrier and exploit the bloodstream to propagate life-threatening metastases through the mesenchymal–epithelial transition. We also explore EMT's significant role in fostering tumour dormancy, senescence, the emergence of cancer stem cells and the formidable challenge of therapeutic resistance. Our review transcends a mere inventory of EMT-inducing elements; it critically assesses the current state of EMT-focused clinical trials, revealing both the hurdles and significant breakthroughs. Highlighting the potential of EMT research, we project its transformative impact on the future of cancer therapy. This exploration is aimed at paving the way towards an era of effectively managing this relentless disease, positioning EMT at the forefront of innovative cancer research strategies.

Keywords

cancer / EMT / exosomes / metastasis / therapeutic

References

[1] GBD 2019 Cancer Risk Factors Collaborators. The global burden of cancer attributable to risk factors, 2010–19: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2022;400:563-591.

[2] Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31-46.

[3] Pedri D, Karras P, Landeloos E, et al. Epithelial-to-mesenchymal-like transition events in melanoma. FEBS J. 2022;289:1352-1368.

[4] Brabletz T, Kalluri R, Nieto MA, et al. EMT in cancer. Nat Rev Cancer. 2018;18:128-134.

[5] Wilson MM, Weinberg RA, Lees JA, Guen VJ. Emerging mechanisms by which EMT programs control stemness. Trends Cancer. 2020;6:775-780.

[6] Zaravinos A. The regulatory role of microRNAs in EMT and cancer. J Oncol. 2015;2015:865816.

[7] Ribatti D, Tamma R, Annese T. Epithelial–mesenchymal transition in cancer: a historical overview. Transl Oncol. 2020;13:100773.

[8] Kim H, Lee S, Shin E, et al. The emerging roles of exosomes as EMT regulators in cancer. Cells. 2020;9:861.

[9] Song KA, Faber AC. Epithelial-to-mesenchymal transition and drug resistance: transitioning away from death. J Thorac Dis. 2019;11:E82-E85.

[10] Cook DP, Vanderhyden BC. Context specificity of the EMT transcriptional response. Nat Commun. 2020;11:2142.

[11] Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008;8:387-398.

[12] Heuberger J, Birchmeier W. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harb Perspect Biol. 2010;2:a002915.

[13] Wu L, Zhao JC, Kim J, et al. ERG is a critical regulator of Wnt/LEF1 signaling in prostate cancer. Cancer Res. 2013;73:6068-6079.

[14] Jayachandran J, Srinivasan H, Mani KP. Molecular mechanism involved in epithelial to mesenchymal transition. Arch Biochem Biophys. 2021;710:108984.

[15] Kang E, Seo J, Yoon H, et al. The post-translational regulation of epithelial–mesenchymal transition-inducing transcription factors in cancer metastasis. Int J Mol Sci. 2021;22:3591.

[16] Deshmukh AP, Vasaikar SV, Tomczak K, et al. Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing. Proc Natl Acad Sci U S A. 2021;118:e2102050118.

[17] Stemmler MP, Eccles RL, Brabletz S, et al. Non-redundant functions of EMT transcription factors. Nat Cell Biol. 2019;21:102-112.

[18] Bolós V, Peinado H, Pérez-Moreno MA, et al. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003;116:499-511.

[19] Georgakopoulos-Soares I, Chartoumpekis DV, Kyriazopoulou V, et al. EMT factors and metabolic pathways in cancer. Front Oncol. 2020;10:499.

[20] Mani SA, Guo W, Liao MJ, et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704-715.

[21] Nassour M, Idoux-Gillet Y, Selmi A, et al. Slug controls stem/progenitor cell growth dynamics during mammary gland morphogenesis. PLoS One. 2012;7:e53498.

[22] Ye X, Tam WL, Shibue T, et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature. 2015;525:256-260.

[23] Gheldof A, Hulpiau P, van Roy F, et al. Evolutionary functional analysis and molecular regulation of the ZEB transcription factors. Cell Mol Life Sci. 2012;69:2527-2541.

[24] Papanikolaou S, Vourda A, Syggelos S, et al. Cell plasticity and prostate cancer: the role of epithelial–mesenchymal transition in tumor progression, invasion, metastasis and cancer therapy resistance. Cancers (Basel). 2021;13:2795.

[25] Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29:4741-4751.

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

[27] Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927-939.

[28] Yang F, Sun L, Li Q, et al. SET8 promotes epithelial–mesenchymal transition and confers TWIST dual transcriptional activities. EMBO J. 2012;31:110-123.

[29] Jing C, Li X, Zhou M, et al. The PSMD14 inhibitor thiolutin as a novel therapeutic approach for esophageal squamous cell carcinoma through facilitating SNAIL degradation. Theranostics. 2021;11:5847-5862.

[30] Gurzu S, Kobori L, Fodor D, et al. Epithelial mesenchymal and endothelial mesenchymal transitions in hepatocellular carcinoma: a review. Biomed Res Int. 2019;2019:2962580.

[31] Salton F, Volpe MC, Confalonieri M. Epithelial–mesenchymal transition in the pathogenesis of idiopathic pulmonary fibrosis. Medicina. 2019;55:83.

[32] Shetty SS, Sharma M, Fonseca FP, et al. Signaling pathways promoting epithelial mesenchymal transition in oral submucous fibrosis and oral squamous cell carcinoma. Jpn Dent Sci Rev. 2020;56:97-108.

[33] Nieszporek A, Skrzypek K, Adamek G, et al. Molecular mechanisms of epithelial to mesenchymal transition in tumor metastasis. Acta Biochim Pol. 2019;66:509-520.

[34] Mylavarapu S, Kumar H, Kumari S, et al. Activation of epithelial–mesenchymal transition and altered β-catenin signaling in a novel Indian colorectal carcinoma cell line. Front Oncol. 2019;9:54.

[35] Razali RA, Lokanathan Y, Yazid MD, et al. Modulation of epithelial to mesenchymal transition signaling pathways by Olea Europaea and its active compounds. Int J Mol Sci. 2019;20:3492.

[36] Wang H, Zhong W, Zhao J, et al. Oleanolic acid inhibits epithelial–mesenchymal transition of hepatocellular carcinoma by promoting iNOS dimerization. Mol Cancer Ther. 2019;18:62-74.

[37] Karimi Roshan M, Soltani A, Soleimani A, et al. Role of AKT and mTOR signaling pathways in the induction of epithelial–mesenchymal transition (EMT) process. Biochimie. 2019;165:229-234.

[38] Jin W. Role of JAK/STAT3 signaling in the regulation of metastasis, the transition of cancer stem cells, and chemoresistance of cancer by epithelial–mesenchymal transition. Cells. 2020;9:217.

[39] Kumar A, Golani A, Kumar LD. EMT in breast cancer metastasis: an interplay of microRNAs, signaling pathways and circulating tumor cells. Front Biosci (Landmark Ed). 2020;25:979-1010.

[40] Shan G, Zhou X, Gu J, et al. Downregulated exosomal microRNA-148b-3p in cancer associated fibroblasts enhance chemosensitivity of bladder cancer cells by downregulating the Wnt/β-catenin pathway and upregulating PTEN. Cell Oncol (Dordr). 2021;44:45-59.

[41] Lai X, Li Q, Wu F, et al. Epithelial–mesenchymal transition and metabolic switching in cancer: lessons from somatic cell reprogramming. Front Cell Dev Biol. 2020;8:760.

[42] Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27-47.

[43] Hirschhaeuser F, Sattler UG, Mueller-Klieser W. Lactate: a metabolic key player in cancer. Cancer Res. 2011;71:6921-6925.

[44] Hamabe A, Konno M, Tanuma N, et al. Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial–mesenchymal transition. Proc Natl Acad Sci U S A. 2014;111:15526-15531.

[45] Jiang F, Ma S, Xue Y, et al. LDH-A promotes malignant progression via activation of epithelial-to-mesenchymal transition and conferring stemness in muscle-invasive bladder cancer. Biochem Biophys Res Commun. 2016;469:985-992.

[46] Morandi A, Taddei ML, Chiarugi P, et al. Targeting the metabolic reprogramming that controls epithelial-to-mesenchymal transition in aggressive tumors. Front Oncol. 2017;7:40.

[47] Attanasio F, Caldieri G, Giacchetti G, et al. Novel invadopodia components revealed by differential proteomic analysis. Eur J Cell Biol. 2011;90:115-127.

[48] Frisch SM, Schaller M, Cieply B. Mechanisms that link the oncogenic epithelial–mesenchymal transition to suppression of anoikis. J Cell Sci. 2013;126:21-29.

[49] Kamarajugadda S, Stemboroski L, Cai Q, et al. Glucose oxidation modulates anoikis and tumor metastasis. Mol Cell Biol. 2012;32:1893-1907.

[50] Blum R, Kloog Y. Metabolism addiction in pancreatic cancer. Cell Death Dis. 2014;5:e1065.

[51] Zhou G, Chiu D, Qin D, et al. The efficacy evaluation of cryosurgery in pancreatic cancer patients with the expression of CD44v6, integrin-β1, CA199, and CEA. Mol Biotechnol. 2012;52:59-67.

[52] Coelho RG, Fortunato RS, Carvalho DP. Metabolic reprogramming in thyroid carcinoma. Front Oncol. 2018;8:82.

[53] An J, Zhang Y, He J, et al. Lactate dehydrogenase A promotes the invasion and proliferation of pituitary adenoma. Sci Rep. 2017;7:4734.

[54] Zhang Y, Lin S, Chen Y, et al. LDH-A promotes epithelial–mesenchymal transition by upregulating ZEB2 in intestinal-type gastric cancer. Oncol Targets Ther. 2018;11:2363-2373.

[55] Rong Y, Wu W, Ni X, et al. Lactate dehydrogenase A is overexpressed in pancreatic cancer and promotes the growth of pancreatic cancer cells. Tumour Biol. 2013;34:1523-1530.

[56] Gaude E, Frezza C. Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival. Nat Commun. 2016;7:13041.

[57] Hardie RA, van Dam E, Cowley M, et al. Mitochondrial mutations and metabolic adaptation in pancreatic cancer. Cancer Metab. 2017;5:2.

[58] Kulawiec M, Owens KM, Singh KK. Cancer cell mitochondria confer apoptosis resistance and promote metastasis. Cancer Biol Ther. 2009;8:1378-1385.

[59] Mannelli M, Rapizzi E, Fucci R, et al. 15 years of paraganglioma: metabolism and pheochromocytoma/paraganglioma. Endocr Relat Cancer. 2015;22:T83-T90.

[60] Xiao M, Yang H, Xu W, et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 2012;26:1326-1338.

[61] Letouzé E, Martinelli C, Loriot C, et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell. 2013;23:739-752.

[62] Castro-Vega LJ, Buffet A, De Cubas AA, et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet. 2014;23:2440-2446.

[63] Clark GR, Sciacovelli M, Gaude E, et al. Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab. 2014;99:E2046-E2050.

[64] Sciacovelli M, Gonçalves E, Johnson TI, et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature. 2016;537:544-547.

[65] Dalmau N, Jaumot J, Tauler R, Bedia C. Epithelial-to-mesenchymal transition involves triacylglycerol accumulation in DU145 prostate cancer cells. Mol Biosyst. 2015;11:3397-3406.

[66] Sánchez-Martínez R, Cruz-Gil S, Gómez de Cedrón M, et al. A link between lipid metabolism and epithelial–mesenchymal transition provides a target for colon cancer therapy. Oncotarget. 2015;6:38719-38736.

[67] Chajès V, Thiébaut AC, Rotival M, et al. Association between serum trans-monounsaturated fatty acids and breast cancer risk in the E3N-EPIC Study. Am J Epidemiol. 2008;167:1312-1320.

[68] Peck B, Schug ZT, Zhang Q, et al. Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments. Cancer Metab. 2016;4:6.

[69] Kato S, Liberona MF, Cerda-Infante J, et al. Simvastatin interferes with cancer ‘stem-cell' plasticity reducing metastasis in ovarian cancer. Endocr Relat Cancer. 2018;25:821-836.

[70] Ramesh V, Brabletz T, Ceppi P. Targeting EMT in cancer with repurposed metabolic inhibitors. Trends Cancer. 2020;6:942-950.

[71] Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281-297.

[72] Cai Y, Yu X, Hu S, et al. A brief review on the mechanisms of miRNA regulation. Genom Proteom Bioinform. 2009;7:147-154.

[73] van Roy F, Berx G. The cell–cell adhesion molecule E-cadherin. Cell Mol Life Sci. 2008;65:3756-3788.

[74] Ma L, Young J, Prabhala H, et al. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol. 2010;12:247-256.

[75] Wang H, Wu Q, Zhang Y, et al. TGF-β1-induced epithelial–mesenchymal transition in lung cancer cells involves upregulation of miR-9 and downregulation of its target, E-cadherin. Cell Mol Biol Lett. 2017;22:22.

[76] Sun L, Yao Y, Liu B, et al. MiR-200b and miR-15b regulate chemotherapy-induced epithelial–mesenchymal transition in human tongue cancer cells by targeting BMI1. Oncogene. 2012;31:432-445.

[77] Wang J, Yao S, Diao Y, et al. miR-15b enhances the proliferation and migration of lung adenocarcinoma by targeting BCL2. Thorac Cancer. 2020;11:1396-1405.

[78] Wang J, Liu H, Tian L, et al. miR-15b inhibits the progression of glioblastoma cells through targeting insulin-like growth factor receptor 1. Horm Cancer. 2017;8:49-57.

[79] Cao M, Seike M, Soeno C, et al. MiR-23a regulates TGF-β-induced epithelial–mesenchymal transition by targeting E-cadherin in lung cancer cells. Int J Oncol. 2012;41:869-875.

[80] Xu H, Sun F, Li X, et al. Down-regulation of miR-23a inhibits high glucose-induced EMT and renal fibrogenesis by up-regulation of SnoN. Hum Cell. 2018;31:22-32.

[81] Zhang Z, Liu S, Shi R, et al. miR-27 promotes human gastric cancer cell metastasis by inducing epithelial-to-mesenchymal transition. Cancer Genet. 2011;204:486-491.

[82] Tan Y, Sangfelt O, Spruck C. The Fbxw7/hCdc4 tumor suppressor in human cancer. Cancer Lett. 2008;271:1-12.

[83] Gebeshuber CA, Zatloukal K, Martinez J. miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Rep. 2009;10:400-405.

[84] Luna C, Li G, Qiu J, et al. Role of miR-29b on the regulation of the extracellular matrix in human trabecular meshwork cells under chronic oxidative stress. Mol Vis. 2009;15:2488-2497

[85] Zhang J, Zhang H, Liu J, et al. miR-30 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in hepatocyte by targeting Snail1. Biochem Biophys Res Commun. 2012;417:1100-1105.

[86] Martello G, Rosato A, Ferrari F, et al. A microRNA targeting dicer for metastasis control. Cell. 2010;141:1195-1207.

[87] Ben Q, Sun Y, Liu J, et al. Nicotine promotes tumor progression and epithelial–mesenchymal transition by regulating the miR-155-5p/NDFIP1 axis in pancreatic ductal adenocarcinoma. Pancreatology. 2020;20:698-708.

[88] Cui L, Lyu Y, Jin X, et al. miR-194 suppresses epithelial–mesenchymal transition of retinal pigment epithelial cells by directly targeting ZEB1. Ann Transl Med. 2019;7:751.

[89] Zhang X, Wei C, Li J, et al. MicroRNA-194 represses glioma cell epithelial-to-mesenchymal transition by targeting Bmi1. Oncol Rep. 2017;37:1593-1600.

[90] Das R, Gregory PA, Fernandes RC, et al. MicroRNA-194 promotes prostate cancer metastasis by inhibiting SOCS2. Cancer Res. 2017;77:1021-1034.

[91] Korpal M, Lee ES, Hu G, et al. The miR-200 family inhibits epithelial–mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 2008;28:14910-14914.

[92] Saydam O, Shen Y, Würdinger T, et al. Downregulated microRNA-200a in meningiomas promotes tumor growth by reducing E-cadherin and activating the Wnt/beta-catenin signaling pathway. Mol Cell Biol. 2009;29:5923-5940.

[93] Park SM, Gaur AB, Lengyel E, et al. 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.

[94] Fan Y, Wang K. miR205 suppresses cell migration, invasion and EMT of colon cancer by targeting mouse double minute 4. Mol Med Rep. 2020;22:633-642.

[95] Liang YK, Lin HY, Dou XW, et al. MiR-221/222 promote epithelial–mesenchymal transition by targeting Notch3 in breast cancer cell lines. NPJ Breast Cancer. 2018;4:20.

[96] Stinson S, Lackner MR, Adai AT, et al. TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer. Sci Signal. 2011;4:ra41.

[97] Hwang MS, Yu N, Stinson SY, et al. miR-221/222 targets adiponectin receptor 1 to promote the epithelial-to-mesenchymal transition in breast cancer. PLoS One. 2013;8:e66502.

[98] Zhang X, Xu X, Ge G, et al. miR498 inhibits the growth and metastasis of liver cancer by targeting ZEB2. Oncol Rep. 2019;41:1638-1648.

[99] Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10:155-159.

[100] Ørom UA, Derrien T, Beringer M, et al. Long noncoding RNAs with enhancer-like function in human cells. Cell. 2010;143:46-58.

[101] Richards EJ, Zhang G, Li ZP, et al. Long non-coding RNAs (LncRNA) regulated by transforming growth factor (TGF) β: lncRNA-hit-mediated TGFβ-induced epithelial to mesenchymal transition in mammary epithelia. J Biol Chem. 2015;290:6857-6867.

[102] Li J, Liu H, Yu J, et al. Chemoresistance to doxorubicin induces epithelial–mesenchymal transition via upregulation of transforming growth factor β signaling in HCT116 colon cancer cells. Mol Med Rep. 2015;12:192-198.

[103] Yuan JH, Yang F, Wang F, et a. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25:666-681.

[104] Zhou M, Hou Y, Yang G, et al. LncRNA-Hh strengthen cancer stem cells generation in twist-positive breast cancer via activation of hedgehog signaling pathway. Stem Cells. 2016;34:55-66.

[105] Shi X, Sun M, Liu H, et al. Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett. 2013;339:159-166.

[106] Hirata H, Hinoda Y, Shahryari V, et al. Long noncoding RNA MALAT1 promotes aggressive renal cell carcinoma through Ezh2 and interacts with miR-205. Cancer Res. 2015;75:1322-1331.

[107] Gupta RA, Shah N, Wang KC, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071-1076.

[108] Kogo R, Shimamura T, Mimori K, et al. Long noncoding RNA Hotair regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 2011;71:6320-6326.

[109] Zhang H, Cai K, Wang J, et al. MiR-7, inhibited indirectly by lincRNA Hotair, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway. Stem Cells. 2014;32:2858-2868.

[110] Ono H, Motoi N, Nagano H, et al. Long noncoding RNA HOTAIR is relevant to cellular proliferation, invasiveness, and clinical relapse in small-cell lung cancer. Cancer Med. 2014;3:632-642.

[111] Wu Y, Zhang L, Wang Y, et al. Long noncoding RNA HOTAIR involvement in cancer. Tumour Biol. 2014;35:9531-9538.

[112] Liu YW, Sun M, Xia R, et al. LincHOTAIR epigenetically silences miR34a by binding to PRC2 to promote the epithelial-to-mesenchymal transition in human gastric cancer. Cell Death Dis. 2015;6:e1802.

[113] Chiyomaru T, Fukuhara S, Saini S, et al. Long non-coding RNA HOTAIR is targeted and regulated by miR-141 in human cancer cells. J Biol Chem. 2014;289:12550-12565.

[114] Guo R, Wu Z, Wang J, et al. Development of a non-coding-RNA-based EMT/CSC inhibitory nanomedicine for in vivo treatment and monitoring of HCC. Adv Sci (Weinh). 2019;6:1801885.

[115] Liu QL, Luo M, Huang C, et al. Epigenetic regulation of epithelial to mesenchymal transition in the cancer metastatic cascade: implications for cancer therapy. Front Oncol. 2021;11:657546.

[116] Lee JY, Kong G. Roles and epigenetic regulation of epithelial–mesenchymal transition and its transcription factors in cancer initiation and progression. Cell Mol Life Sci. 2016;73:4643-4660.

[117] Cardenas H, Vieth E, Lee J, et al. TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells. Epigenetics. 2014;9:1461-1472.

[118] Lin YT, Wu KJ. Epigenetic regulation of epithelial–mesenchymal transition: focusing on hypoxia and TGF-β signaling. J Biomed Sci. 2020;27:39.

[119] Si W, Huang W, Zheng Y, et al. Dysfunction of the reciprocal feedback loop between GATA3-and ZEB2-nucleated repression programs contributes to breast cancer metastasis. Cancer Cell. 2015;27:822-836.

[120] Pistore C, Giannoni E, Colangelo T, et al. DNA methylation variations are required for epithelial-to-mesenchymal transition induced by cancer-associated fibroblasts in prostate cancer cells. Oncogene. 2017;36:5551-5566.

[121] Serrano-Gomez SJ, Maziveyi M, Alahari SK. Regulation of epithelial–mesenchymal transition through epigenetic and post-translational modifications. Mol Cancer. 2016;15:18.

[122] Chung VY, Tan TZ, Ye J, et al. The role of GRHL2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells. Commun Biol. 2019;2:272.

[123] Skrypek N, Goossens S, De Smedt E, et al. Epithelial-to-mesenchymal transition: epigenetic reprogramming driving cellular plasticity. Trends Genet. 2017;33:943-959.

[124] Dong B, Qiu Z, Wu Y. Tackle epithelial–mesenchymal transition with epigenetic drugs in cancer. Front Pharmacol. 2020;11:596239.

[125] Eckschlager T, Plch J, Stiborova M, et al. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci. 2017;18:1414.

[126] Shivji GG, Dhar R, Devi A. Role of exosomes and its emerging therapeutic applications in the pathophysiology of non-infectious diseases. Biomarkers. 2022;27:534-548.

[127] Kumar S, Dhar R, Kumar LBSS, et al. Theranostic signature of tumor-derived exosomes in cancer. Med Oncol. 2023;40:321.

[128] You J, Li M, Cao LM, et al. Snail1-dependent cancer-associated fibroblasts induce epithelial–mesenchymal transition in lung cancer cells via exosomes. QJM. 2019;112:581-590.

[129] Hardin H, Helein H, Meyer K, et al. Thyroid cancer stem-like cell exosomes: regulation of EMT via transfer of lncRNAs. Lab Invest. 2018;98:1133-1142.

[130] Dhar R, Devi A, Gorai S, et al. Exosome and epithelial–mesenchymal transition: a complex secret of cancer progression. J Cell Mol Med. 2023;27:1603-1607.

[131] Tian T, Han J, Huang J, et al. Hypoxia-induced intracellular and extracellular heat shock protein gp96 increases paclitaxel-resistance and facilitates immune evasion in breast cancer. Front Oncol. 2021;11:784777.

[132] Goulet CR, Champagne A, Bernard G, et al. Cancer-associated fibroblasts induce epithelial–mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling. BMC Cancer. 2019;19:137.

[133] García-Heredia JM, Otero-Albiol D, Pérez M, et al. Breast tumor cells promotes the horizontal propagation of EMT, stemness, and metastasis by transferring the MAP17 protein between subsets of neoplastic cells. Oncogenesis. 2020;9:96.

[134] Li K, Liu T, Chen J, et al. Survivin in breast cancer-derived exosomes activates fibroblasts by up-regulating SOD1, whose feedback promotes cancer proliferation and metastasis. J Biol Chem. 2020;295:13737-13752.

[135] Hoshino A, Costa-Silva B, Shen TL, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329-335.

[136] Tian W, Liu S, Li B. Potential role of exosomes in cancer metastasis. Biomed Res Int. 2019;2019:4649705.

[137] Ghosh S, Dhar R, Gurudas Shivji G, et al. Clinical impact of exosomes in colorectal cancer metastasis. ACS Appl Bio Mater. 2023;6:2576-2590.

[138] Hoque S, Dhar R, Kar R, et al. Cancer stem cells (CSCs): key player of radiotherapy resistance and its clinical significance. Biomarkers. 2023;28:139-151.

[139] Ge Q, Zhou Y, Lu J, et al. miRNA in plasma exosome is stable under different storage conditions. Molecules. 2014;19(2):1568-1575.

[140] Yang B, Feng X, Liu H, et al. High-metastatic cancer cells derived exosomal miR92a-3p promotes epithelial–mesenchymal transition and metastasis of low-metastatic cancer cells by regulating PTEN/Akt pathway in hepatocellular carcinoma. Oncogene. 2020;39:6529-6543.

[141] Wang H, Wei H, Wang J, et al. MicroRNA-181d-5p-containing exosomes derived from CAFs promote EMT by regulating CDX2/HOXA5 in breast cancer. Mol Ther Nucleic Acids. 2020;19:654-667.

[142] Zhao S, Mi Y, Guan B, et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol. 2020;13:156.

[143] Wang D, Wang X, Si M, et al. Exosome-encapsulated miRNAs contribute to CXCL12/CXCR4-induced liver metastasis of colorectal cancer by enhancing M2 polarization of macrophages. Cancer Lett. 2020;474:36-52.

[144] Wu P, Cai J, Chen Q, et al. Lnc-TALC promotes O⁶-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p. Nat Commun. 2019;10:2045.

[145] Zhou L, Li J, Tang Y, et al. Exosomal LncRNA LINC00659 transferred from cancer-associated fibroblasts promotes colorectal cancer cell progression via miR-342-3p/ANXA2 axis. J Transl Med. 2021;19:8.

[146] Liang ZX, Liu HS, Wang FW, et al. LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization. Cell Death Dis. 2019;10:829.

[147] Huang CS, Ho JY, Chiang JH, et al. Exosome-derived LINC00960 and LINC02470 promote the epithelial–mesenchymal transition and aggressiveness of bladder cancer cells. Cells. 2020;9:1419.

[148] Zhang X, Wang S, Wang H, et al. Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway. Mol Cancer. 2019;18:20.

[149] Chen T, Liu Y, Li C, et al. Tumor-derived exosomal circFARSA mediates M2 macrophage polarization via the PTEN/PI3K/AKT pathway to promote non-small cell lung cancer metastasis. Cancer Treat Res Commun. 2021;28:100412.

[150] Wei S, Zheng Y, Jiang Y, et al. The circRNA circPTPRA suppresses epithelial–mesenchymal transitioning and metastasis of NSCLC cells by sponging miR-96-5p. EBioMedicine. 2019;44:182-193.

[151] Hong W, Xue M, Jiang J, et al. Circular RNA circ-CPA4/let-7 miRNA/PD-L1 axis regulates cell growth, stemness, drug resistance and immune evasion in non-small cell lung cancer (NSCLC). J Exp Clin Cancer Res. 2020;39:149.

[152] Chen J, Rong N, Liu M, et al. The exosome-circ_0001359 derived from cigarette smoke exposed-prostate stromal cells promotes epithelial cells collagen deposition and primary ciliogenesis. Toxicol Appl Pharmacol. 2022;435:115850.

[153] Bhattacharya B, Dhar R, Mukherjee S, et al. Exosome DNA: an untold story of cancer. Clin Transl Disc. 2023;3:e218.

[154] Dhar R, Gorai S, Devi A, et al. Exosome: a megastar of future cancer personalized and precision medicine. Clin Transl Disc. 2023;3:e208.

[155] Krishnan A, Bhattacharya B, Mandal D, et al. Salivary exosomes: a theranostics secret of oral cancer—correspondence. Int J Surg. 2022;108: 106990.

[156] Dhar R, Mukerjee N, Mukherjee D, et al. Plant-derived exosomes: a new dimension in cancer therapy. Phytother Res. 2023.

[157] Dhar R, Bhattacharya B, Mandal D, et al. Exosome-based cancer vaccine: a cutting-edge approach—correspondence. Int J Surg. 2022;108:106993.

[158] Dhar R, Gorai S, Devi A, et al. Decoding of exosome heterogeneity for cancer theranostics. Clin Transl Med. 2023;13:e1288.

[159] Dhar R, Devi A. Exosomes barcoding: a smart approach for cancer liquid biopsy. J Liquid Biopsy. 2023;2:100129.

[160] Gundamaraju R, Lu W, Paul MK, et al. Autophagy and EMT in cancer and metastasis: who controls whom? Biochim Biophys Acta Mol Basis Dis. 2022;1868:166431.

[161] Greten FR, Grivennikov SI. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity. 2019;51:27-41.

[162] Bocci F, Gearhart-Serna L, Boareto M, et al. Toward understanding cancer stem cell heterogeneity in the tumor microenvironment. Proc Natl Acad Sci U S A. 2019;116:148-157.

[163] Aiello NM, Kang Y. Context-dependent EMT programs in cancer metastasis. J Exp Med. 2019;216:1016-1026.

[164] Aggarwal V, Montoya CA, Donnenberg VS, et al. Interplay between tumor microenvironment and partial EMT as the driver of tumor progression. iScience. 2021;24:102113.

[165] Taki M, Abiko K, Ukita M, et al. Tumor immune microenvironment during epithelial–mesenchymal transition. Clin Cancer Res. 2021;27:4669-4679.

[166] Gómez-Valenzuela F, Escobar E, Pérez-Tomás R, et al. The inflammatory profile of the tumor microenvironment, orchestrated by cyclooxygenase-2, promotes epithelial–mesenchymal transition. Front Oncol. 2021;11:686792.

[167] Saxena K, Jolly MK, Balamurugan K. Hypoxia, partial EMT and collective migration: emerging culprits in metastasis. Transl Oncol. 2020;13:100845.

[168] Lee SY, Ju MK, Jeon HM, et al. Reactive oxygen species induce epithelial–mesenchymal transition, glycolytic switch, and mitochondrial repression through the Dlx2/Snail signaling pathways in MCF7 cells. Mol Med Rep. 2019;20:2339-2346.

[169] Steinbichler TB, Savic D, Dudás J, et al. Cancer stem cells and their unique role in metastatic spread. Semin Cancer Biol. 2020;60:148-156.

[170] Arnold CR, Mangesius J, Skvortsova II, et al. The role of cancer stem cells in radiation resistance. Front Oncol. 2020;10:164.

[171] Shakib H, Rajabi S, Dehghan MH, et al. Epithelial-to-mesenchymal transition in thyroid cancer: a comprehensive review. Endocrine. 2019;66:435-455.

[172] Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017;14:611-629.

[173] Kalluri R, Weinberg RA. The basics of epithelial–mesenchymal transition. J Clin Invest. 2009;119:1420-1428.

[174] Zeisberg M, Shah AA, Kalluri R. Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J Biol Chem. 2005;280:8094-8100.

[175] Terry S, Savagner P, Ortiz-Cuaran S, et al. New insights into the role of EMT in tumor immune escape. Mol Oncol. 2017;11:824-846.

[176] Smit MA, Peeper DS. Deregulating EMT and senescence: double impact by a single twist. Cancer Cell. 2008;14:5-7.

[177] Weinberg RA. Twisted epithelial–mesenchymal transition blocks senescence. Nat Cell Biol. 2008;10:1021-1023.

[178] Arima Y, Inoue Y, Shibata T, et al. Rb depletion results in deregulation of E-cadherin and induction of cellular phenotypic changes that are characteristic of the epithelial-to-mesenchymal transition. Cancer Res. 2008;68:5104-5112.

[179] Morel AP, Lièvre M, Thomas C, et al. Generation of breast cancer stem cells through epithelial–mesenchymal transition. PLoS One. 2008;3(8):e2888.

[180] Guo W, Keckesova Z, Donaher JL, et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell. 2012;148:1015-1028.

[181] Wang X, Zheng M, Liu G, et al. Krüppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Res. 2007;67:7184-7193.

[182] Lu Z, Ghosh S, Wang Z, et al. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell. 2003;4:499-515.

[183] Pastushenko I, Blanpain C. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 2019;29:212-226.

[184] Thiery JP, Acloque H, Huang RY, et al. Epithelial–mesenchymal transitions in development and disease. Cell. 2009;139:871-890.

[185] Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275-292.

[186] Kim DH, Xing T, Yang Z, et al. Epithelial mesenchymal transition in embryonic development, tissue repair and cancer: a comprehensive overview. J Clin Med. 2017;7:1.

[187] Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442-454.

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

[189] Yang J, Antin P, Berx G, et al. EMT International Association (TEMTIA). Guidelines and definitions for research on epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2020;21:341-352.

[190] Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and cancer progression. Science. 2020;368:eaaw5473.

[191] Shi ZD, Pang K, Wu ZX, et al. Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies. Signal Transduct Target Ther. 2023;8:113.

[192] Ribatti D, Tamma R, Annese T. Epithelial–mesenchymal transition in cancer: a historical overview. Transl Oncol. 2020;13:100773.

[193] Abba ML, Patil N, Leupold JH, et al. MicroRNA regulation of epithelial to mesenchymal transition. J Clin Med. 2016;5:8.

[194] Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486-541.

[195] Chen J, Han Q, Pei D. EMT and MET as paradigms for cell fate switching. J Mol Cell Biol. 2012;4:66-69.

[196] Radisky DC. Epithelial–mesenchymal transition. J Cell Sci. 2005;118:4325-4326.

[197] Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial–mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172:973-981.

[198] De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97-110.

[199] Kaufhold S, Bonavida B. Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res. 2014;33:62.

[200] Vu T, Datta PK. Regulation of EMT in colorectal cancer: a culprit in metastasis. Cancers (Basel). 2017;9:171.

[201] Lin YT, Wu KJ. Epigenetic regulation of epithelial–mesenchymal transition: focusing on hypoxia and TGF-β signaling. J Biomed Sci. 2020;2:39.

[202] Qin S, Jiang J, Lu Y, et al. Emerging role of tumor cell plasticity in modifying therapeutic response. Signal Transduct Target Ther. 2020;5:228.

[203] Carnino JM, Ni K, Jin Y. Post-translational modification regulates formation and cargo-loading of extracellular vesicles. Front Immunol. 2020;11:948.

[204] Jiang J, Wang K, Chen Y, et al. Redox regulation in tumor cell epithelial–mesenchymal transition: molecular basis and therapeutic strategy. Signal Transduct Target Ther. 2017;2:17036.

[205] Nisticò P, Bissell MJ, Radisky DC. Epithelial–mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. Cold Spring Harb Perspect Biol. 2012;4:a011908.

[206] Gaponova AV, Rodin S, Mazina AA, et al. Epithelial–mesenchymal transition: role in cancer progression and the perspectives of antitumor treatment. Acta Nat. 2020;12:4-23.

[207] Huang Y, Hong W, Wei X. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol. 2022;15:129.

[208] Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265-273.

[209] Reymond N, d'Água BB, Ridley AJ. Crossing the endothelial barrier during metastasis. Nat Rev Cancer. 2013;13:858-870.

[210] Lok C. Imaging: cancer caught in the act. Nature. 2014;509:148-149.

[211] Pignatelli J, Bravo-Cordero JJ, Roh-Johnson M, et al. Macrophage-dependent tumor cell transendothelial migration is mediated by Notch1/Mena^INV-initiated invadopodium formation. Sci Rep. 2016;6:37874.

[212] Harney AS, Arwert EN, Entenberg D, et al. Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 2015;5:932-943.

[213] Hoeres T, Wilhelm M, Smetak M, et al. Immune cells regulate VEGF signalling via release of VEGF and antagonistic soluble VEGF receptor-1. Clin Exp Immunol. 2018;192:54-67.

[214] Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology. 2005;69:4-10.

[215] Viski C, König C, Kijewska M, et al. Endosialin-expressing pericytes promote metastatic dissemination. Cancer Res. 2016;76:5313-5325.

[216] Eckert MA, Lwin TM, Chang AT, et al. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell. 2011;19:372-386.

[217] Eckert MA, Yang J. Targeting invadopodia to block breast cancer metastasis. Oncotarget. 2011;2:562-568.

[218] Cheung KJ, Gabrielson E, Werb Z, et al. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell. 2013;155:1639-1651.

[219] Aceto N, Bardia A, Miyamoto DT, et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014;158:1110-1122.

[220] Pantel K, Speicher MR. The biology of circulating tumor cells. Oncogene. 2016;35:1216-1224.

[221] Pantel K, Alix-Panabières C, Riethdorf S. Cancer micrometastases. Nat Rev Clin Oncol. 2009;6:339-351.

[222] Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781-791.

[223] idard FC, Peeters DJ, Fehm T, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 2014;15:406-414.

[224] Alix-Panabières C, Mader S, Pantel K. Epithelial–mesenchymal plasticity in circulating tumor cells. J Mol Med (Berl). 2017;95:133-142.

[225] Alix-Panabières C, Pantel K. Circulating tumor cells: liquid biopsy of cancer. Clin Chem. 2013;59:110-118.

[226] Barriere G, Fici P, Gallerani G, et al. Circulating tumor cells and epithelial, mesenchymal and stemness markers: characterization of cell subpopulations. Ann Transl Med. 2014;2:109.

[227] Khoo BL, Lee SC, Kumar P, et al. Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy. Oncotarget. 2015;6:15578-15593.

[228] Mego M, Mani SA, Lee BN, et al. Expression of epithelial–mesenchymal transition-inducing transcription factors in primary breast cancer: the effect of neoadjuvant therapy. Int J Cancer. 2012;130:808-816.

[229] Fischer KR, Durrans A, Lee S, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527:472-476.

[230] Zheng X, Carstens JL, Kim J, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527:525-530.

[231] Tsai JH, Donaher JL, Murphy DA, et al. Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell. 2012;22:725-736.

[232] Mittal V. Epithelial mesenchymal transition in tumor metastasis. Annu Rev Pathol. 2018;13:395-412.

[233] Nieto MA, Huang RY, Jackson RA, et al. EMT: 2016. Cell. 2016;166:21-45.

[234] Chao Y, Wu Q, Acquafondata M, et al. Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenviron. 2012;5:19-28.

[235] Rodriguez FJ, Lewis-Tuffin LJ, Anastasiadis PZ. E-cadherin's dark side: possible role in tumor progression. Biochim Biophys Acta. 2012;1826:23-31.

[236] Kowalski PJ, Rubin MA, Kleer CG. E-cadherin expression in primary carcinomas of the breast and its distant metastases. Breast Cancer Res. 2003;5:R217-R222.

[237] Kleer CG, van Golen KL, Braun T, et al. Persistent E-cadherin expression in inflammatory breast cancer. Mod Pathol. 2001;14:458-464.

[238] Colpaert CG, Vermeulen PB, Benoy I, et al. Inflammatory breast cancer shows angiogenesis with high endothelial proliferation rate and strong E-cadherin expression. Br J Cancer. 2003;88:718-725.

[239] Gong Y. Pathologic aspects of inflammatory breast cancer: Part 2. Biologic insights into its aggressive phenotype. Semin Oncol. 2008;35:33-40.

[240] Gao D, Joshi N, Choi H, et al. Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res. 2012;72:1384-1394.

[241] Esposito M, Mondal N, Greco TM, et al. Bone vascular niche E-selectin induces mesenchymal–epithelial transition and Wnt activation in cancer cells to promote bone metastasis. Nat Cell Biol. 2019;21:627-639.

[242] Sundfeldt K, Piontkewitz Y, Ivarsson K, et al. E-cadherin expression in human epithelial ovarian cancer and normal ovary. Int J Cancer. 1997;74:275-280.

[243] Davidson B, Berner A, Nesland JM, et al. E-cadherin and alpha-, beta-, and gamma-catenin protein expression is up-regulated in ovarian carcinoma cells in serous effusions. J Pathol. 2000;192(4):460-469.

[244] Rhim AD, Mirek ET, Aiello NM, et al. EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148:349-361.

[245] Pei D, Shu X, Gassama-Diagne A, et al. Mesenchymal–epithelial transition in development and reprogramming. Nat Cell Biol. 2019;21:44-53.

[246] Yao D, Dai C, Peng S. Mechanism of the mesenchymal–epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9:1608-1620.

[247] Frisch SM, Farris JC, Pifer PM. Roles of Grainyhead-like transcription factors in cancer. Oncogene. 2017;36:6067-6073.

[248] Roca H, Hernandez J, Weidner S, et al. Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer. PLoS One. 2013;8:e76773.

[249] May CD, Sphyris N, Evans KW, et al. Epithelial–mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression. Breast Cancer Res. 2011;13:202.

[250] Scheel C, Weinberg RA. Phenotypic plasticity and epithelial–mesenchymal transitions in cancer and normal stem cells? Int J Cancer. 2011;129:2310-2314.

[251] Korpal M, Ell BJ, Buffa FM, et al. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med. 2011;17:1101-1108.

[252] Wang Z, Li Y, Kong D, et al. Acquisition of epithelial–mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 2009;69:2400-2407.

[253] Fan F, Samuel S, Evans KW, et al. Overexpression of snail induces epithelial–mesenchymal transition and a cancer stem cell-like phenotype in human colorectal cancer cells. Cancer Med. 2012;1:5-16.

[254] Rasheed ZA, Yang J, Wang Q, et al. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst. 2010;102(5):340-351.

[255] Chen Y, Shao Z, Jiang E, et al. CCL21/CCR7 interaction promotes EMT and enhances the stemness of OSCC via a JAK2/STAT3 signaling pathway. J Cell Physiol. 2020;235:5995-6009.

[256] Akbar MW, Isbilen M, Belder N, et al. A stemness and EMT based gene expression signature identifies phenotypic plasticity and is a predictive but not prognostic biomarker for breast cancer. J Cancer. 2020;11:949-961.

[257] Ding Q, Miyazaki Y, Tsukasa K, et al. CD133 facilitates epithelial–mesenchymal transition through interaction with the ERK pathway in pancreatic cancer metastasis. Mol Cancer. 2014;13:15.

[258] Oskarsson T, Batlle E, Massagué J. Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell. 2014;14:306-321.

[259] Vega S, Morales AV, Ocaña OH, et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004;18:1131-1143.

[260] Emanuele MJ, Ciccia A, Elia AE, et al. Proliferating cell nuclear antigen (PCNA)-associated KIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate. Proc Natl Acad Sci U S A. 2011;108:9845-9850.

[261] Blick T, Widodo E, Hugo H, et al. Epithelial mesenchymal transition traits in human breast cancer cell lines. Clin Exp Metastasis. 2008;25:629-642.

[262] Weidenfeld K, Schif-Zuck S, Abu-Tayeh H, et al. Dormant tumor cells expressing LOXL2 acquire a stem-like phenotype mediating their transition to proliferative growth. Oncotarget. 2016;7:71362-71377.

[263] Ansieau S, Bastid J, Doreau A, et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell. 2008;14:79-89.

[264] Ohashi S, Natsuizaka M, Wong GS, et al. Epidermal growth factor receptor and mutant p53 expand an esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors. Cancer Res. 2010;70:4174-4184.

[265] Coppé JP, Patil CK, Rodier F, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6:2853-2868.

[266] Yuan A, Chen JJ, Yao PL, et al. The role of interleukin-8 in cancer cells and microenvironment interaction. Front Biosci. 2005;10:853-865.

[267] Laberge RM, Awad P, Campisi J, et al. Epithelial–mesenchymal transition induced by senescent fibroblasts. Cancer Microenviron. 2012;5:39-44.

[268] De Las Rivas J, Brozovic A, Izraely S, et al. Cancer drug resistance induced by EMT: novel therapeutic strategies. Arch Toxicol. 2021;95:2279-2297.

[269] Huang J, Li H, Ren G. Epithelial–mesenchymal transition and drug resistance in breast cancer (Review). Int J Oncol. 2015;47:840-848.

[270] McConkey DJ, Choi W, Marquis L, et al. Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer. Cancer Metastasis Rev. 2009;28:335-344.

[271] Arumugam T, Ramachandran V, Fournier KF, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820-5828.

[272] Lindner D. Animal models and the tumor microenvironment: studies of tumor-host symbiosis. Semin Oncol. 2014;41:146-155.

[273] Wu Y, Ginther C, Kim J, et al. Expression of Wnt3 activates Wnt/β-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells. Mol Cancer Res. 2012;10:1597-1606.

[274] Della Corte CM, Bellevicine C, Vicidomini G, et al. SMO gene amplification and activation of the hedgehog pathway as novel mechanisms of resistance to anti-epidermal growth factor receptor drugs in human lung cancer. Clin Cancer Res. 2015;21:4686-4697.

[275] Haslehurst AM, Koti M, Dharsee M, et al. EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer. 2012;12:91.

[276] Debnath P, Huirem RS, Dutta P, et al. Epithelial–mesenchymal transition and its transcription factors. Biosci Rep. 2022;42:BSR20211754.

[277] Knott SRV, Wagenblast E, Khan S, et al. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature. 2018;554:378-381.

[278] Gupta PB, Pastushenko I, Skibinski A, et al. Phenotypic plasticity: driver of cancer initiation, progression, and therapy resistance. Cell Stem Cell. 2019;24:65-78.

[279] Phi LTH, Sari IN, Yang YG, et al. Cancer stem cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells Int. 2018;2018:5416923.

[280] Farahzadi R, Valipour B, Fathi E, et al. Oxidative stress regulation and related metabolic pathways in epithelial–mesenchymal transition of breast cancer stem cells. Stem Cell Res Ther. 2023;14:342.

[281] Chou MY, Yang MH. Interplay of immunometabolism and epithelial–mesenchymal transition in the tumor microenvironment. Int J Mol Sci. 2021;22:9878.

[282] Du B, Shim JS. Targeting epithelial–mesenchymal transition (EMT) to overcome drug resistance in cancer. Molecules. 2016;21:965.

[283] Seo J, Ha J, Kang E, et al. The role of epithelial–mesenchymal transition-regulating transcription factors in anti-cancer drug resistance. Arch Pharm Res. 2021;44:281-292.

[284] Imodoye SO, Adedokun KA, Muhammed AO, et al. Understanding the complex milieu of epithelial–mesenchymal transition in cancer metastasis: new insight into the roles of transcription factors. Front Oncol. 2021;11:762817.

[285] Pastushenko I, Brisebarre A, Sifrim A, et al. Identification of the tumour transition states occurring during EMT. Nature. 2018;556:463-468.

[286] Zeisberg M, Neilson EG. Biomarkers for epithelial–mesenchymal transitions. J Clin Invest. 2009;119:1429-1437.

[287] Williams ED, Gao D, Redfern A, et al. Controversies around epithelial–mesenchymal plasticity in cancer metastasis. Nat Rev Cancer. 2019;19:716-732.

[288] Stark TW, Hensley PJ, Spear A, et al. Predictive value of epithelial–mesenchymal-transition (EMT) signature and PARP-1 in prostate cancer radioresistance. Prostate. 2017;77:1583-1591.

[289] Gilles C, Polette M, Piette J, et al. Vimentin expression in cervical carcinomas: association with invasive and migratory potential. J Pathol. 1996;180:175-180. lt;175::AID-PATH630>3.0.CO;2-G

[290] Puram SV, Tirosh I, Parikh AS, et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell. 2017;171:1611-1624.e24.

[291] Tan TZ, Miow QH, Miki Y, et al. Epithelial–mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol Med. 2014;6:1279-1293.

[292] Ting DT, Wittner BS, Ligorio M, et al. Single-cell RNA sequencing identifies extracellular matrix gene expression by pancreatic circulating tumor cells. Cell Rep. 2014;8:1905-1918.

[293] Mak MP, Tong P, Diao L, et al. A patient-derived, pan-cancer EMT signature identifies global molecular alterations and immune target enrichment following epithelial-to-mesenchymal transition. Clin Cancer Res. 2016;22:609-620.

[294] Rokavec M, Kaller M, Horst D, et al. Pan-cancer EMT-signature identifies RBM47 down-regulation during colorectal cancer progression. Sci Rep. 2017;7:4687.

[295] Payne RE, Wang F, Su N, et al. Viable circulating tumour cell detection using multiplex RNA in situ hybridisation predicts progression-free survival in metastatic breast cancer patients. Br J Cancer. 2012;106:1790-1797.

[296] Decalf J, Albert ML, Ziai J. New tools for pathology: a user's review of a highly multiplexed method for in situ analysis of protein and RNA expression in tissue. J Pathol. 2019;247:650-661.

[297] Stylianou N, Lehman ML, Wang C, et al. A molecular portrait of epithelial–mesenchymal plasticity in prostate cancer associated with clinical outcome. Oncogene. 2019;38:913-934.

[298] Davis FM, Stewart TA, Thompson EW, et al. Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol Sci. 2014;35:479-488.

[299] Jonckheere S, Adams J, De Groote D, et al. Epithelial–mesenchymal transition (EMT) as a therapeutic target. Cells Tissues Organs. 2022;211:157-182.

[300] Derynck R, Budi EH. Specificity, versatility, and control of TGF-β family signaling. Sci Signal. 2019;12:eaav5183.

[301] Fabregat I, Fernando J, Mainez J, et al. TGF-beta signaling in cancer treatment. Curr Pharm Des. 2014;20:2934-2947.

[302] Chua KN, Sim WJ, Racine V, et al. A cell-based small molecule screening method for identifying inhibitors of epithelial–mesenchymal transition in carcinoma. PLoS One. 2012;7:e33183.

[303] Sim WJ, Iyengar PV, Lama D, et al. c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression. Nat Commun. 2019;10:4349.

[304] Meidhof S, Brabletz S, Lehmann W, et al. ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat. EMBO Mol Med. 2015;7:831-847.

[305] Cook N, Basu B, Smith DM, et al. A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. Br J Cancer. 2018;118:793-801.

[306] Connolly RM, Rudek MA, Piekarz R. Entinostat: a promising treatment option for patients with advanced breast cancer. Future Oncol. 2017;13:1137-1148.

[307] Joseph C, Alsaleem M, Orah N, et al. Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival. Breast Cancer Res Treat. 2020;182:267-282.

[308] Hu H, Li B, Zhou C, et al. Diagnostic value of WIF1 methylation for colorectal cancer: a meta-analysis. Oncotarget. 2018;9:5378-5386.

[309] Shang S, Hua F, Hu ZW. The regulation of β-catenin activity and function in cancer: therapeutic opportunities. Oncotarget. 2017;8:33972-33989.

[310] Avilés-Gaxiola S, Gutiérrez-Grijalva EP, León-Felix J, et al. Peptides in colorectal cancer: current state of knowledge. Plant Foods Hum Nutr. 2020;75:467-476.

[311] Gingras D, Batist G, Béliveau R. AE-941 (Neovastat): a novel multifunctional antiangiogenic compound. Expert Rev Anticancer Ther. 2001;1:341-347.

[312] Gao W, Chan JY, Wei WI, et al. Anti-cancer effects of curcumin on head and neck cancers. Anticancer Agents Med Chem. 2012;12:1110-1116.

[313] Charkhchi P, Cybulski C, Gronwald J, et al. CA125 and ovarian cancer: a comprehensive review. Cancers (Basel). 2020;12:3730.

[314] Bell-McGuinn KM, Matthews CM, Ho SN, et al. A phase II, single-arm study of the anti-α5β1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer. Gynecol Oncol. 2011;121:273-279.

[315] Kawai A, Naka N, Shimomura A, et al. Efficacy and safety of TAS-115, a novel oral multi-kinase inhibitor, in osteosarcoma: an expansion cohort of a phase I study. Invest New Drugs. 2021;39:1559-1567.

[316] McDonald OG, Maitra A, Hruban RH. Human correlates of provocative questions in pancreatic pathology. Adv Anat Pathol. 2012;19:351-362.

[317] Hartwell KA, Muir B, Reinhardt F, et al. The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proc Natl Acad Sci U S A. 2006;103:18969-18974.

[318] Heerboth S, Housman G, Leary M, et al. EMT and tumor metastasis. Clin Transl Med. 2015;4:6.

[319] Iwatsuki M, Mimori K, Yokobori T, et al. Epithelial–mesenchymal transition in cancer development and its clinical significance. Cancer Sci. 2010;101:293-299.

[320] Radisky DC, Levy DD, Littlepage LE, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005;436:123-127.

[321] Gonzalez DM, Medici D. Signaling mechanisms of the epithelial–mesenchymal transition. Sci Signal. 2014;7:re8.

[322] Thiery JP. Epithelial–mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15:740-746.

[323] Noor J, Chaudhry A, Noor R, et al. Advancements and applications of liquid biopsies in oncology: a narrative review. Cureus. 2023;15:e42731.

[324] Desai N, Katare P, Makwana V, et al. Tumor-derived systems as novel biomedical tools—turning the enemy into an ally. Biomater Res. 2023;27:113.

[325] Kiesslich T, Pichler M, Neureiter D. Epigenetic control of epithelial–mesenchymal-transition in human cancer. Mol Clin Oncol. 2013;1:3-11.

[326] Kang H, Kim H, Lee S, et al. Role of metabolic reprogramming in epithelial–mesenchymal transition (EMT). Int J Mol Sci. 2019;20:2042.

[327] Pal AK, Sharma P, Zia A, et al. Metabolomics and EMT markers of breast cancer: a crosstalk and future perspective. Pathophysiology. 2022;29:200-222.

[328] Cheng YQ, Wang SB, Liu JH, et al. Modifying the tumour microenvironment and reverting tumour cells: new strategies for treating malignant tumours. Cell Prolif. 2020;53:e12865.

[329] Zhong W, Sun T. Editorial: epithelial–mesenchymal transition (EMT) as a therapeutic target in cancer. Front Oncol. 2023;13:1121416.

[330] Tiwari N, Gheldof A, Tatari M, et al. EMT as the ultimate survival mechanism of cancer cells. Semin Cancer Biol. 2012;22:194-207.

[331] Huang Z, Zhang Z, Zhou C, et al. Epithelial–mesenchymal transition: the history, regulatory mechanism, and cancer therapeutic opportunities. MedComm. 2022;3:e144.

[332] Wei Q, Qian Y, Yu J, Wong CC. Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications. Oncogene. 2020;39:6139-6156.

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