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Polyploid giant cancer cells, stemness and epithelial-mesenchymal plasticity elicited by human cytomegalovirus

Abstract

A growing body of evidence is recognizing human cytomegalovirus (HCMV) as a potential oncogenic virus. We hereby provide the first experimental in vitro evidence for HCMV as a reprogramming vector, through the induction of dedifferentiation of mature human mammary epithelial cells (HMECs), generation of a polyploid giant cancer cell (PGCC) phenotype characterized by sustained growth of blastomere-like cells, in concordance with the acquisition of embryonic stem cells characteristics and epithelial-mesenchymal plasticity. HCMV presence parallels the succession of the observed cellular and molecular events potentially ensuing the transformation process. Correlation between PGCCs detection and HCMV presence in breast cancer tissue further validates our hypothesis in vivo. Our study indicates that some clinical HCMV strains conserve the potential to transform HMECs and fit with a “blastomere-like” model of oncogenesis, which may be relevant in the pathophysiology of breast cancer and other adenocarcinoma, especially of poor prognosis.

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Fig. 1: Activation of oncogenic pathways, differential apoptosis rates and upregulation of telomerase activity in HMECs infected by HCMV clinical strains.
Fig. 2: Colony formation in soft agar, chronic infection of HMECs with HCMV clinical isolates and the appearance of distinct cellular features of the giant cell cycle including polyploid giant cancer cells (PGCCs).
Fig. 3: Detection of polyploidy, anchorage-independent growth and proliferative capacity of CTH cells.
Fig. 4: Phenotypic characterization of CTH cells.
Fig. 5: Mammospheres formation and detection of embryonic stem cells markers in CTH cells.
Fig. 6: Detection of replicative HCMV in CTH culture.
Fig. 7: Transcriptomic analysis of CTH cells, PGCCs detection and correlation with HCMV in human breast tumor biopsies.
Fig. 8: Potential model depicting the course of events leading to the initiation of the giant cell cycle, dedifferentiation, stemness and epithelial-to-mesenchymal/mesenchymal-to-epithelial transitions following HCMV infection.

Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information files and from the corresponding authors on request.

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Acknowledgements

This work was supported by grants from the University of Franche-Comté, and the Région Franche-Comté. Z.N. is a recipient of a doctoral scholarship from the municipality of Habbouch. The funders had no role in the data collection, analysis, patient recruitment, or decision to publish. We thank DImaCell Imaging Ressource Center, University of Bourgogne Franche-Comté, Faculty of Health Sciences, 25000 Besançon, France for technical support.

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ZN, SP, SHA, AC, CM, FM performed experiments. GH, M-PA., OA, MDA, JPF participated to the data analysis. GH conceived and designed the project. ZN, SP, JPF, GH wrote the manuscript.

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Correspondence to Georges Herbein.

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Nehme, Z., Pasquereau, S., Haidar Ahmad, S. et al. Polyploid giant cancer cells, stemness and epithelial-mesenchymal plasticity elicited by human cytomegalovirus. Oncogene 40, 3030–3046 (2021). https://doi.org/10.1038/s41388-021-01715-7

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