Epithelial cell adhesion molecule-centered, bioinformatics and machine learning-based meta-analysis for the identification of pan-cancer epithelial-mesenchymal markers for circulating tumor cells

Paper Details

Research Paper 18/09/2025
Views (11)
current_issue_feature_image
publication_file

Epithelial cell adhesion molecule-centered, bioinformatics and machine learning-based meta-analysis for the identification of pan-cancer epithelial-mesenchymal markers for circulating tumor cells

Shubham Singh, GR Brindha, Nagarajan Rajendra Prasad
Int. J. Biosci. 27(3), 145-157, September 2025.
Copyright Statement: Copyright 2025; The Author(s).
License: CC BY-NC 4.0

Abstract

Advances in bioinformatics have greatly contributed to the discovery of epithelial–mesenchymal transition (EMT) markers, such as epithelial cell adhesion molecule (EPCAM). This study aimed to conduct an EPCAM-centered meta-analyses of previously RNA-sequencing data for identifying pan-cancer EMT markers in circulating tumor cells (CTCs) utilizing bioinformatics- and machine learning (ML)-based approaches. In this study, the RNA sequencing data of seven different cancer types from two datasets, namely GSE273023 and GSE274442, were analyzed. Gene–gene correlation among included cancer samples and EPCAM-centered gene–gene correlation analysis were performed. The data were subjected to ML-based pathway and gene clustering analysis. Notably, the results showed that most of the cancers presented similar gene expression profile, albeit with some differences, which were primarily attributed to differences in mitochondrial gene expression. Furthermore, gene–gene correlation analysis revealed multiple genes with significantly altered expression, including CBWD2, MED23, QRSL1, ZNF568, and INTU. Similarly, TRPS1 was found to be significantly correlated with EPCAM. Overall, the findings of this study reveal the association between EPCAMTRPS1 and CBWD2-associated MED23QRSL1ZNF568INTU axes, thereby showing their potential as co-markers and for the development of multiplexed immunoassay for a robust pan-cancer CTC detection approach.

Ahmadieh-Yazdi A, Mahdavinezhad A, Tapak L, Nouri F, Taherkhani A, Afshar S. 2023. Using machine learning approach for screening metastatic biomarkers in colorectal cancer and predictive modeling with experimental validation. Scientific Reports 13, 19426. https://doi.org/10.1038/s41598-023-46633-8

Allison KH, Sledge GW. 2014. Heterogeneity and cancer. Oncology (Williston Park) 28, 772–778.

Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. 2021. Introduction to meta-analysis (2nd ed.). John Wiley & Sons.

Chan HYE, Chen ZS. 2022. Multifaceted investigation underlies diverse mechanisms contributing to the downregulation of Hedgehog pathway-associated genes INTU and IFT88 in lung adenocarcinoma and uterine corpus endometrial carcinoma. Aging 14, 7794–7823. https://doi.org/10.18632/aging.204262

Dongre A, Weinberg RA. 2019. New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nature Reviews Molecular Cell Biology 20, 69–84. https://doi.org/10.1038/s41580-018-0080-4

Dursun F, Genc HM, Mine Yılmaz A, Tas I, Eser M, Pehlivanoglu C, Yilmaz BK, Guran T. 2022. Primary adrenal insufficiency in a patient with biallelic QRSL1 mutations. European Journal of Endocrinology 187, K27–K32. https://doi.org/10.1530/EJE-22-0233

Ferlay J, Ervik M, Lam F, Laversanne M, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F. 2024. Global Cancer Observatory: Cancer today. Lyon, France: International Agency for Research on Cancer. https://gco.iarc.who.int/today

Garg M. 2013. Epithelial-mesenchymal transition-activating transcription factors: Multifunctional regulators in cancer. World Journal of Stem Cells 5, 188.https://doi.org/10.4252/wjsc.v5.i4.188

Gerstberger S, Jiang Q, Ganesh K. 2023. Metastasis. Cell 186, 1564–1579. https://doi.org/10.1016/j.cell.2023.03.003

Gröger CJ, Grubinger M, Waldhör T, Vierlinger K, Mikulits W. 2012. Meta-analysis of gene expression signatures defining the epithelial to mesenchymal transition during cancer progression. PLoS ONE 7, e51136. https://doi.org/10.1371/journal.pone.0051136

Groot Koerkamp B, Rahbari NN, Büchler MW, Koch M, Weitz J. 2013. Circulating tumor cells and prognosis of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer: A meta-analysis. Annals of Surgical Oncology 20, 2156–2165. https://doi.org/10.1245/s10434-013-2907-8

Guven DC, Sahin TK, Erul E, Kilickap S, Gambichler T, Aksoy S. 2022. The association between the pan-immune-inflammation value and cancer prognosis: A systematic review and meta-analysis. Cancers 14, 2675. https://doi.org/10.3390/cancers14112675

Han CW, Jeong MS, Jang SB. 2024. Influence of the interaction between p53 and ZNF568 on mitochondrial oxidative phosphorylation. International Journal of Biological Macromolecules 275, 133314. https://doi.org/10.1016/j.ijbiomac.2024.133314

Hong J, Sun J, Huang T. 2013. Increased expression of TRPS1 affects tumor progression and correlates with patients’ prognosis of colon cancer. BioMed Research International 2013, 1–6. https://doi.org/10.1155/2013/454085

Hung RJ, Ulrich CM, Goode EL, Brhane Y, Muir K, Chan AT, Marchand LLe, Schildkraut J, Witte JS, Eeles R, Boffetta P, Spitz MR, Poirier JG, Rider DN, Fridley BL, Chen Z, Haiman C, Schumacher F, Easton DF, Landi MT, Brennan P, Houlston R, Christiani DC, Field JK, Bickeböller H, Risch A, Kote-Jarai Z, Wiklund F, Grönberg H, Chanock S, Berndt SI, Kraft P, Lindström S, Al Olama AA, Song H, Phelan C, Wentzensen N, Peters U, Slattery ML; GECCO; Sellers TA; FOCI; Casey G, Gruber SB; CORECT; Hunter DJ; DRIVE; Amos CI, Henderson B; GAME-ON Network. 2015. Cross cancer genomic investigation of inflammation pathway for five common cancers: Lung, ovary, prostate, breast, and colorectal cancer. Journal of the National Cancer Institute 107, djv246. https://doi.org/10.1093/jnci/djv246

Hussain I, Nataliani Y, Ali M, Hussain A, Mujlid HM, Almaliki FA, Rahimi NM. 2024. Weighted multiview K-means clustering with L2 regularization. Symmetry 16, 1646. https://doi.org/10.3390/sym16121646

Lamouille S, Xu J, Derynck R. 2014. Molecular mechanisms of epithelial–mesenchymal transition. Nature Reviews Molecular Cell Biology 15, 178–196. https://doi.org/10.1038/nrm3758

Lee D, Park Y, Kim S. 2021. Towards multi-omics characterization of tumor heterogeneity: A comprehensive review of statistical and machine learning approaches. Briefings in Bioinformatics 22, bbaa188. https://doi.org/10.1093/bib/bbaa188

Lee JY, Lee K, Seo BK, Cho KR, Woo OH, Song SE, Kim E-K, Lee HY, Kim JS, Cha J. 2022. Radiomic machine learning for predicting prognostic biomarkers and molecular subtypes of breast cancer using tumor heterogeneity and angiogenesis properties on MRI. European Radiology 32, 650–660. https://doi.org/10.1007/s00330-021-08146-8

Liao Z, Zhou W. 2025a. RNA-seq of vertebral metastatic tumor samples from pan-cancer primary tumors. Gene Expression Omnibus (GEO) database (Accession Number GSE273023).

Liao Z, Zhou W. 2025b. RNA-seq of vertebral metastatic tumor samples from pan-cancer primary tumors II. Gene Expression Omnibus (GEO) database (Accession Number GSE274442).

Liu W, Li Z, Luo Z, Liao W, Liu Z, Liu J. 2021. Machine learning for the prediction of bone metastasis in patients with newly diagnosed thyroid cancer. Cancer Medicine 10, 2802–2811. https://doi.org/10.1002/cam4.3776

Lv Q, Gong L, Zhang T, Ye J, Chai L, Ni C, Mao Y. 2016. Prognostic value of circulating tumor cells in metastatic breast cancer: A systemic review and meta-analysis. Clinical and Translational Oncology 18, 322–330. https://doi.org/10.1007/s12094-015-1372-1

Malla SB, Byrne RM, Lafarge MW, Corry SM, Fisher NC, Tsantoulis PK, Mills ML, Ridgway RA, Lannagan TRM, Najumudeen AK, Gilroy KL, Amirkhah R, Maguire SL, Mulholland EJ, Belnoue-Davis HL, Grassi E, Viviani M, Rogan E, Redmond KL, Sakhnevych S, McCooey AJ, Bull C, Hoey E, Sinevici N, Hall H, Ahmaderaghi B, Domingo E, Blake A, Richman SD, Isella C, Miller C, Bertotti A, Trusolino L, Loughrey MB, Kerr EM, Tejpar S; S:CORT consortium; Maughan TS, Lawler M, Campbell AD, Leedham SJ, Koelzer VH, Sansom OJ, Dunne PD. 2024. Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer. Nature Genetics 56, 458–472. https://doi.org/10.1038/s41588-024-01654-5

Roggli VL, Vollmer RT, Greenberg SD, McGavran MH, Spjut HJ, Yesner R. 1985. Lung cancer heterogeneity: A blinded and randomized study of 100 consecutive cases. Human Pathology 16, 569–579. https://doi.org/10.1016/S0046-8177(85)80106-4

Rosati D, Palmieri M, Brunelli G, Morrione A, Iannelli F, Frullanti E, Giordano A. 2024. Differential gene expression analysis pipelines and bioinformatic tools for the identification of specific biomarkers: A review. Computational and Structural Biotechnology Journal 23, 1154–1168. https://doi.org/10.1016/j.csbj.2024.02.018

Shah SNA, Parveen R. 2025. Differential gene expression analysis and machine learning identified structural, TFs, cytokine and glycoproteins, including SOX2, TOP2A, SPP1, COL1A1, and TIMP1 as potential drivers of lung cancer. Biomarkers 30, 200–215. https://doi.org/10.1080/1354750X.2025.2461698

Shi J, Liu H, Yao F, Zhong C, Zhao H. 2014. Upregulation of mediator MED23 in non-small-cell lung cancer promotes the growth, migration, and metastasis of cancer cells. Tumor Biology 35, 12005–12013. https://doi.org/10.1007/s13277-014-2499-3

Stinson S, Lackner MR, Adai AT, Yu N, Kim H-J, O’Brien C, Spoerke J, Jhunjhunwala S, Boyd Z, Januario T, Newman RJ, Yue P, Bourgon R, Modrusan Z, Stern HM, Warming S, de Sauvage FJ, Amler L, Yeh R-F, Dornan D. 2011. TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer. Science Signaling 4, ra41. https://doi.org/10.1126/scisignal.2001538

Sun Z, Chung D, Neelon B, MillarWilson A, Ethier SP, Xiao F, Zheng Y, Wallace K, Hardiman G. 2023. A Bayesian framework for pathway‐guided identification of cancer subgroups by integrating multiple types of genomic data. Statistics in Medicine 42, 5266–5284. https://doi.org/10.1002/sim.9911

Vera-Yunca D, Girard P, Parra-Guillen ZP, Munafo A, Trocóniz IF, Terranova N. 2020. Machine learning analysis of individual tumor lesions in four metastatic colorectal cancer clinical studies: Linking tumor heterogeneity to overall survival. The AAPS Journal 22, 58. https://doi.org/10.1208/s12248-020-0434-7

Wang C, Yang Y, Yin L, Wei N, Hong T, Sun Z, Yao J, Li Z, Liu T. 2020. Novel potential biomarkers associated with epithelial to mesenchymal transition and bladder cancer prognosis identified by integrated bioinformatic analysis. Frontiers in Oncology 10, 931. https://doi.org/10.3389/fonc.2020.00931

Wang H, Shen L, Li Y, Lv J. 2020. Integrated characterisation of cancer genes identifies key molecular biomarkers in stomach adenocarcinoma. Journal of Clinical Pathology 73, 579–586. https://doi.org/10.1136/jclinpath-2019-206400

Wang X, Li X, Jiang W. 2023. High expression of RTN4IP1 predicts adverse prognosis for patients with breast cancer. Translational Cancer Research 12, 859–872. https://doi.org/10.21037/tcr-22-2350

Wu F, Fan J, He Y, Xiong A, Yu J, Li Y, Zhang Y, Zhao W, Zhou F, Li W, Zhang J, Zhang X, Qiao M, Gao G, Chen S, Chen X, Li X, Hou L, Wu C, Su C, Ren S, Odenthal M, Buettner R, Fang N, Zhou C. 2021. Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer. Nature Communications 12, 2540. https://doi.org/10.1038/s41467-021-22801-0

Yeung KT, Yang J. 2017. Epithelial–mesenchymal transition in tumor metastasis. Molecular Oncology 11, 28–39. https://doi.org/10.1002/1878-0261.12017

Yousef M, Ozdemir F, Jaber A, Allmer J, Bakir-Gungor B. 2023. PriPath: Identifying dysregulated pathways from differential gene expression via grouping, scoring, and modeling with an embedded feature selection approach. BMC Bioinformatics 24, 60. https://doi.org/10.1186/s12859-023-05187-2

Zhang J, Wu L-Y, Zhang X-S, Zhang S. 2014. Discovery of co-occurring driver pathways in cancer. BMC Bioinformatics 15, 271. https://doi.org/10.1186/1471-2105-15-271

Related Articles

Spatio-temporal dynamics of the physical and chemical parameters of lake Ehuikro

Nahon Mamadou Fofana, Kouassi Koumoin Henry, Appiah Yao Saki, Diomande Abou, Int. J. Biosci. 27(3), 158-168, September 2025.

Bridging education and action: Student-driven experiential learning in achieving sustainable development goals

Nagamani Bora, Bhambra, Jyotkanwal, Carbajo Muro, Cayetano, Chauhan, Kunga, Desai, Shayna, Estes, Grace, Gurung, Manasvi, Kulkarni, Smriti, Mendonca, Hazel, Mukundan, Krtin, Mulyawan, Rainer Dave, Nnadi Dominion Chiemerie, Rajasekharan, Sathvika, Saha, Swarnadeep, Tolksdorff, Mikayla, Tran, Giao, Wade-Baylis, Lucinda, Int. J. Biosci. 27(3), 136-144, September 2025.

Phytochemical, proximate, anti-inflammatory and antimicrobial activity of Psidium guajava

G. Saranya, K. Durgadevi, V. Ramamurthy, Int. J. Biosci. 27(3), 129-135, September 2025.

Effects of soil preparation techniques and organic-mineral fertilization on maize (Zea mays L.) yields in western Burkina Faso in the context of climate change

Traore Adama, Saba Fatimata, Traore Karim, Bandaogo Arzouma Alimata, Bazongo Pascal, Traore Ouola, Int. J. Biosci. 27(3), 107-115, September 2025.

Fecundity and gonadosomatic index of Macrobrachium australe (Guérin-Méneville, 1838) in Dohinob Dacu River

Mary Jhea O. Culanculan, Arrah Jane T. Senia, Ma. Dulce C. Guillena, Int. J. Biosci. 27(3), 96-101, September 2025.

Production management and marketing of sweet potato (Ipomea batatas (L.) Lam) in a farm environment in South Benin

Manhognon Oscar Euloge Faton, Zaki Bonou-Gbo, Hervé Soura, Mahutin Mariano Djihoulandé, Fanou Lucie, Léopold Simplice Gnancadja, Int. J. Biosci. 27(3), 88-95, September 2025.