Lack of extracellular matrix switches TGF-β induced apoptosis of endometrial cells to epithelial to mesenchymal transition

• Published in: Scientific reports Vol. 12; no. 1; p. 14821
• Main Authors: Ruiz-Mitjana, Anna, Navaridas, Raúl, Vidal-Sabanés, Maria, Perramon-Güell, Aida, Yeramian, Andree, Felip, Isidre, Eritja, Núria, Egea, Joaquim, Encinas, Mario, Matias-Guiu, Xavier, Dolcet, Xavier
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67; 631/80; AKT protein; Apoptosis; Carcinogenesis; Endometrium; Epithelial cells; Extracellular matrix; Homeostasis; Humanities and Social Sciences; Mesenchyme; multidisciplinary; Phenotypes; Polarity; Science; Science (multidisciplinary); Smad2 protein; Transforming growth factor-b; Tumor suppressor genes
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-18976-1

The extracellular matrix and the correct establishment of epithelial cell polarity plays a critical role in epithelial cell homeostasis and cell polarity. In addition, loss of tissue structure is a hallmark of carcinogenesis. In this study, we have addressed the role of extracellular matrix in the cellular responses to TGF-β. It is well known that TGF-β is a double-edged sword: it acts as a tumor suppressor in normal epithelial cells, but conversely has tumor-promoting effects in tumoral cells. However, the factors that determine cellular outcome in response to TGF-β remain controversial. Here, we have demonstrated that the lack of extracellular matrix and consequent loss of cell polarity inhibits TGF-β-induced apoptosis, observed when endometrial epithelial cells are polarized in presence of extracellular matrix. Rather, in absence of extracellular matrix, TGF-β-treated endometrial epithelial cells display features of epithelial-to-mesenchymal transition. We have also investigated the molecular mechanism of such a switch in cellular response. On the one hand, we found that the lack of Matrigel results in increased AKT signaling which is sufficient to inhibit TGF-β-induced apoptosis. On the other hand, we demonstrate that TGF-β-induced epithelial-to-mesenchymal transition requires ERK and SMAD2/3 activation. In summary, we demonstrate that loss of cell polarity changes the pro-apoptotic function of TGF-β to tumor-associated phenotype such as epithelial-to-mesenchymal transition. These results may be important for understanding the dual role of TGF-β in normal versus tumoral cells.