Phosphatidylserine modulation influences syncytia formation in human breast cancer cell lines
Year: 2026
Type: article
Abstract: Background Cell-cell fusion is a biological process, crucial for the development and homeostasis of tissue. In contrast, cell fusion is also pathologically associated with viral infections or cancer cell fusion. While physiological cell fusion is strictly regulated, is it not clear how and why cancer cells fuse with other cells. Since the resulting cancer hybrid cells can have new malignant properties, like chemotherapeutic resistance or an enhanced metastatic potential, it is of interest to get to know how cancer cell fusion takes place. Methods A breast cancer cell fusion model, relying on the dual split protein cell fusion assay and overexpression of the fusogen Syncytin-1, was used to study the impact of the membrane lipid phosphatidylserine (PS) and lipid distributing proteins. Therefore, the breast epithelial cell line M13SV1 was cocultured with the breast cancer cell lines MDA-MB-231 or HS578T. To mask PS, we added the PS-binding protein Annexin V in the coculturing medium. The most prominent expressed scramblase Ano6/TMEM16F was investigated using the clinically used substances Niclosamide, Clofazimine, Salinomycin and Hexachlorophene to indirectly or directly inhibit the protein’s activity. In addition, Ano6 was knocked-out using CRISPR/Cas9. The flippase Atp8a1 was simultaneously overexpressed with its cofactor CDC50a and assays assessing the tumorigenic properties as well as the cell fusion capacity of the differently treated or altered cells were done. Results While Annexin V was able to significantly decrease Syncytin-1-mediated cell fusion, the four substances Niclosamide, Clofazimine, Salinomycin and Hexachlorophene did not affect the amount of phosphatidylserine on the cells’ surface or their capacity to fuse with other cells. The Ano6/TMEM16F KO as well as the Atp8a1-CDC50a overexpression showed rather non-significant effects on the cell fusion. Conclusion Although the effects were mainly non-significant, it was shown, that Syncytin-1-mediated cell fusion could be decreased when M13SV1 cells overexpressing Syncytin-1 were overexpressing Atp8a1-CDC50a, suggesting that less PS in the membrane of these cells is causing the decrease in cell fusion. Vice versa, the loss of Ano6 or the overexpression of Atp8a1-CDC50a in the breast cancer cell lines was able to increase Syncytin-1-mediated cell fusion. This suggests the hypothesis that the localization of PS during fusion may be dynamic and that externalized PS may enhance the function of Syncytin-1 on the expressing cell, while it appears to disrupt cell fusion when exposed on the neighboring cell.
Source: BMC Cancer
Institution: Witten/Herdecke University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,390
OpenAlex ID: W7225743392
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