Abstract
Genotoxic drugs used to treat cancer can trigger senescence, which contributes to chemotherapy resistance and tumor heterogeneity. However, the resulting cellular and molecular alterations following senescence remain poorly characterized. In this study, chemotherapy-induced senescence was triggered by etoposide in MDA-MB-231 breast cancer cells, and their fibrogenic potential, epithelial-to-mesenchymal transition (EMT), and stemness features were examined. In these cells, key mediators of fibrosis were significantly upregulated, suggesting a profibrotic potential involving TGF-β signaling. Etoposide also accentuated the mesenchymal phenotype of MDA-MB-231 cells and increased their motility. Additionally, nuclear β-catenin accumulation and upregulation of its EMT target genes were observed in senescent cells, alongside increased stemness markers, indicating a plastic cellular state involving Wnt/β-catenin signaling. Interestingly, pharmacological inhibition of the TGF-β/Wnt/β-catenin pathways reduced fibrosis, EMT, stemness marker expression, and cell migration, suggesting that these pathways are key regulators of these processes in senescent cells. These findings provide new insights into the molecular mechanisms driving chemotherapy-induced senescence and highlight these pathways as potential targets to alleviate resistance and aggressiveness in breast cancer.
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This research was funded by the Lebanese American University (LAU) under grant number PIRF-I0087 and supported by intramural funds from the Department of Biological Sciences (LAU) to secure space, equipment, and consumables.
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M.R. designed the study and was responsible for funding acquisition, methodology, project administration and supervision. M.E.S., E.A., M.D., J.S., M.B., M.A., A.A., and M.R. performed and analyzed the experiments. M.R. prepared the figures and wrote the manuscript with input from all the authors. All authors have read and agreed to the published version of the manuscript.
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El Samarji, M., Alam, E., Dakramanji, M. et al. Crosstalk between TGF-β and Wnt/β-catenin signaling drives fibrogenic and stem-like phenotypes in senescent MDA-MB-231 breast cancer cells. npj Aging (2026). https://doi.org/10.1038/s41514-025-00322-0
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DOI: https://doi.org/10.1038/s41514-025-00322-0
