Involvement of immune system and Epithelial–Mesenchymal-Transition in increased invasiveness of clustered circulatory tumor cells in breast cancer

Abstract Background Circulating tumor cells (CTCs) are the critical initiators of distant metastasis formation. In which, the reciprocal interplay among different metastatic pathways and their metastasis driver genes which promote survival of CTCs is not well introduced using network approaches. Met...

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Autores principales:	Samane Khoshbakht, Sadegh Azimzadeh Jamalkandi, Ali Masudi-Nejad
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Breast cancer Single/cluster CTC Metastasis Directed network Epithelial-mesenchymal transition Immune response Internal medicine RC31-1245 Genetics QH426-470
Acceso en línea:	https://doaj.org/article/e3588a792d0742b0a8182074ffab12c8
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spelling	oai:doaj.org-article:e3588a792d0742b0a8182074ffab12c82021-11-21T12:04:24ZInvolvement of immune system and Epithelial–Mesenchymal-Transition in increased invasiveness of clustered circulatory tumor cells in breast cancer10.1186/s12920-021-01112-91755-8794https://doaj.org/article/e3588a792d0742b0a8182074ffab12c82021-11-01T00:00:00Zhttps://doi.org/10.1186/s12920-021-01112-9https://doaj.org/toc/1755-8794Abstract Background Circulating tumor cells (CTCs) are the critical initiators of distant metastasis formation. In which, the reciprocal interplay among different metastatic pathways and their metastasis driver genes which promote survival of CTCs is not well introduced using network approaches. Methods Here, to investigate the unknown pathways of single/cluster CTCs, the co-expression network was reconstructed, using WGCNA (Weighted Correlation Network Analysis) method. Having used the hierarchical clustering, we detected the Immune-response and EMT subnetworks. The metastatic potential of genes was assessed and validated through the support vector machine (SVM), neural network, and decision tree methods on two external datasets. To identify the active signaling pathways in CTCs, we reconstructed a casual network. The Log-Rank test and Kaplan–Meier curve were applied to detect prognostic gene signatures for distant metastasis-free survival (DMFS). Finally, a predictive model was developed for metastasis risk of patients using VIF-stepwise feature selection. Results Our results showed the crosstalk among EMT, the immune system, menstrual cycles, and the stemness pathway in CTCs. In which, fluctuation of menstrual cycles is a new detected pathway in breast cancer CTCs. The reciprocal association between immune responses and EMT was identified in CTCs. The SVM model indicated a high metastatic potential of EMT subnetwork (accuracy, sensitivity, and specificity scores were 87%). The DMFS model was identified to predict patients’ metastasis risks. (c-index = 0.7). Finally, novel metastatic biomarkers of KRT18 and KRT19 were detected in breast cancer CTCs. Conclusions In conclusion, the reciprocal interplay among critical unknown pathways in CTCs manifests both their survival in blood and metastatic potentials. Such findings may help to develop more precise predictive metastatic-risk models or detect pivotal metastatic biomarkers.Samane KhoshbakhtSadegh Azimzadeh JamalkandiAli Masudi-NejadBMCarticleBreast cancerSingle/cluster CTCMetastasisDirected networkEpithelial-mesenchymal transitionImmune responseInternal medicineRC31-1245GeneticsQH426-470ENBMC Medical Genomics, Vol 14, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Breast cancer Single/cluster CTC Metastasis Directed network Epithelial-mesenchymal transition Immune response Internal medicine RC31-1245 Genetics QH426-470
spellingShingle	Breast cancer Single/cluster CTC Metastasis Directed network Epithelial-mesenchymal transition Immune response Internal medicine RC31-1245 Genetics QH426-470 Samane Khoshbakht Sadegh Azimzadeh Jamalkandi Ali Masudi-Nejad Involvement of immune system and Epithelial–Mesenchymal-Transition in increased invasiveness of clustered circulatory tumor cells in breast cancer
description	Abstract Background Circulating tumor cells (CTCs) are the critical initiators of distant metastasis formation. In which, the reciprocal interplay among different metastatic pathways and their metastasis driver genes which promote survival of CTCs is not well introduced using network approaches. Methods Here, to investigate the unknown pathways of single/cluster CTCs, the co-expression network was reconstructed, using WGCNA (Weighted Correlation Network Analysis) method. Having used the hierarchical clustering, we detected the Immune-response and EMT subnetworks. The metastatic potential of genes was assessed and validated through the support vector machine (SVM), neural network, and decision tree methods on two external datasets. To identify the active signaling pathways in CTCs, we reconstructed a casual network. The Log-Rank test and Kaplan–Meier curve were applied to detect prognostic gene signatures for distant metastasis-free survival (DMFS). Finally, a predictive model was developed for metastasis risk of patients using VIF-stepwise feature selection. Results Our results showed the crosstalk among EMT, the immune system, menstrual cycles, and the stemness pathway in CTCs. In which, fluctuation of menstrual cycles is a new detected pathway in breast cancer CTCs. The reciprocal association between immune responses and EMT was identified in CTCs. The SVM model indicated a high metastatic potential of EMT subnetwork (accuracy, sensitivity, and specificity scores were 87%). The DMFS model was identified to predict patients’ metastasis risks. (c-index = 0.7). Finally, novel metastatic biomarkers of KRT18 and KRT19 were detected in breast cancer CTCs. Conclusions In conclusion, the reciprocal interplay among critical unknown pathways in CTCs manifests both their survival in blood and metastatic potentials. Such findings may help to develop more precise predictive metastatic-risk models or detect pivotal metastatic biomarkers.
format	article
author	Samane Khoshbakht Sadegh Azimzadeh Jamalkandi Ali Masudi-Nejad
author_facet	Samane Khoshbakht Sadegh Azimzadeh Jamalkandi Ali Masudi-Nejad
author_sort	Samane Khoshbakht
title	Involvement of immune system and Epithelial–Mesenchymal-Transition in increased invasiveness of clustered circulatory tumor cells in breast cancer
title_short	Involvement of immune system and Epithelial–Mesenchymal-Transition in increased invasiveness of clustered circulatory tumor cells in breast cancer
title_full	Involvement of immune system and Epithelial–Mesenchymal-Transition in increased invasiveness of clustered circulatory tumor cells in breast cancer
title_fullStr	Involvement of immune system and Epithelial–Mesenchymal-Transition in increased invasiveness of clustered circulatory tumor cells in breast cancer
title_full_unstemmed	Involvement of immune system and Epithelial–Mesenchymal-Transition in increased invasiveness of clustered circulatory tumor cells in breast cancer
title_sort	involvement of immune system and epithelial–mesenchymal-transition in increased invasiveness of clustered circulatory tumor cells in breast cancer
publisher	BMC
publishDate	2021
url	https://doaj.org/article/e3588a792d0742b0a8182074ffab12c8
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Involvement of immune system and Epithelial–Mesenchymal-Transition in increased invasiveness of clustered circulatory tumor cells in breast cancer

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