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Constitutive proteasomal degradation of TWIST-1 in epithelial–ovarian cancer stem cells impacts differentiation and metastatic potential

Oncogene volume 32, pages 39–49 (2013)Cite this article

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Abstract

Epithelial–mesenchymal transition (EMT) is a critical process for embryogenesis but is abnormally activated during cancer metastasis and recurrence. This process enables epithelial cancer cells to acquire mobility and traits associated with stemness. It is unknown whether epithelial stem cells or epithelial cancer stem cells are able to undergo EMT, and what molecular mechanism regulates this process in these specific cell types. We found that epithelial–ovarian cancer stem cells (EOC stem cells) are the source of metastatic progenitor cells through a differentiation process involving EMT and mesenchymal–epithelial transition (MET). We demonstrate both in vivo and in vitro the differentiation of EOC stem cells into mesenchymal spheroid-forming cells (MSFCs) and their capacity to initiate an active carcinomatosis. Furthermore, we demonstrate that human EOC stem cells injected intraperitoneally in mice are able to form ovarian tumors, suggesting that the EOC stem cells have the ability to ‘home’ to the ovaries and establish tumors. Most interestingly, we found that TWIST-1 is constitutively degraded in EOC stem cells, and that the acquisition of TWIST-1 requires additional signals that will trigger the differentiation process. These findings are relevant for understanding the differentiation and metastasis process in EOC stem cells.

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Acknowledgements

This study was supported in part by grants from NCI/NIH RO1CA127913, RO1CA118678, The Janet Burros Memorial Foundation, The Sands Family Foundation and the Discovery To Cure Research Program. GY was supported by the Brozman Foundation. Special thanks to Dr Ernst-Martin Fuchtbauer for the plasmids, pEMSV, pEMSV-TWIST1 and pEMSV-E12; and to Dr Wange Lu for the plasmid pFUIGW.

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  1. Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, New Haven, CT, USA

    G Yin, A B Alvero, V Craveiro, J C Holmberg, H-H Fu, M K Montagna, Y Yang, I Chefetz-Menaker, S Nuti, M Rossi, D-A Silasi, T Rutherford & G Mor

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Yin, G., Alvero, A., Craveiro, V. et al. Constitutive proteasomal degradation of TWIST-1 in epithelial–ovarian cancer stem cells impacts differentiation and metastatic potential. Oncogene 32, 39–49 (2013). https://doi.org/10.1038/onc.2012.33

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