Wnt/ERK/CDK4/6 activation in the partial EMT state coordinates mammary cancer stemness with self-renewal and inhibition of differentiation Journal Article
| Authors: | Liang, H. Z.; Benard, O.; Kumar, V.; Griffen, A.; Ren, Z.; Sivalingam, K.; Wang, J. L.; Benito, E. D.; Zhang, X. S.; Zhang, J. H.; Suyama, K.; LaFave, L. M.; Norton, L.; Hazan, R. B. |
| Article Title: | Wnt/ERK/CDK4/6 activation in the partial EMT state coordinates mammary cancer stemness with self-renewal and inhibition of differentiation |
| Abstract: | BackgroundThe hybrid EMT state is a key driver of tumour regenerative and metastatic potential; however, the mechanism whereby this programme regulates tumour stemness with respect to self-renewal and differentiation remains unclear.MethodsWe isolated epithelial/mesenchymal (E/M) (CD104highCD44high) and mesenchymal (M) (CD104low CD44high) subpopulations from basal-like breast cancer cell lines. These were assayed for tumour-initiating potential and organoid-forming ability, as well as for transcriptional regulators of the hybrid EMT state by RNA and ATAC-sequencing, and their regulation by the Wnt/ERK/CDK4/6 signalling pathway.ResultsE/M cells were endowed with organoid-forming ability as well as by tumour-initiating and metastatic potential relative to M cells. Interestingly, Wnt3a stimulates transient ERK/CDK4/6 activation in E/M cells, thereby upregulating FOXC2, and in turn TAp63 and Delta Np63, which support the hybrid state. In parallel, ERK/CDK4/6 activates S-phase and FOXM1, thereby promoting self-renewal. Remarkably, transient ERK activation by Wnt3a deactivates EGFR, thus preventing sustained ERK phosphorylation from causing E/M differentiation. Consistently, ERK/CDK4/6 drug perturbation in E/M cells suppressed FOXC2/p63, FOXM1, self-renewal, organoid formation and mammary tumour growth via epithelial differentiation.ConclusionsThese findings unravelled a mechanism whereby the hybrid EMT state regulates stemness, self-renewal and differentiation via transient Wnt/ERK/CDK4/6 activation, which can be leveraged for cancer-stem cell therapy. |
| Keywords: | protein; down-regulation; phosphorylation; expression; cells; program; pathway; mechanisms; transcription-factor; transitions |
| Journal Title: | British Journal of Cancer |
| ISSN: | 0007-0920 |
| Publisher: | Nature Publishing Group |
| Publication status: | Online ahead of print |
| Date Published: | 2025-01-01 |
| Online Publication Date: | 2025-01-01 |
| Language: | English |
| ACCESSION: | WOS:001544137900001 |
| DOI: | 10.1038/s41416-025-03074-6 |
| PROVIDER: | wos |
| Notes: | Article; Early Access -- Source: Wos |
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