Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple‐negative breast cancer

摘要

Epithelial–mesenchymal transition (EMT) and its reverse process, mesenchymal–epithelial transition MET, are crucial in several stages of cancer metastasis. Epithelial–mesenchymal transition allows cancer cells to move to proximal blood vessels for intravasation. However, because EMT and MET processes are dynamic, mesenchymal cancer cells are likely to undergo MET transiently and subsequently re‐undergo EMT to restart the metastatic process. Therefore, spatiotemporally coordinated mutual regulation between EMT and MET could occur during metastasis. To elucidate such regulation, we chose HCC38, a human triple‐negative breast cancer cell line, because HCC38 is composed of epithelial and mesenchymal populations at a fixed ratio even though mesenchymal cells proliferate significantly more slowly than epithelial cells. We purified epithelial and mesenchymal cells from Venus‐labeled and unlabeled HCC38 cells and mixed them at various ratios to follow EMT and MET. Using this system, we found that the efficiency of EMT is approximately an order of magnitude higher than that of MET and that the two populations significantly enhance the transition of cells from the other population to their own. In addition, knockdown of Zinc finger E‐box‐binding homeobox 1 (ZEB1) or Zinc finger protein style="fixed-case">SNAI2 ( style="fixed-case">SLUG) significantly suppressed style="fixed-case">EMT but promoted partial style="fixed-case">MET, indicating that style="fixed-case">ZEB1 and style="fixed-case">SLUG are crucial to style="fixed-case">EMT and style="fixed-case">MET. We also show that primary breast cancer cells underwent style="fixed-case">EMT that correlated with changes in expression profiles of genes determining style="fixed-case">EMT status and breast cancer subtype. These changes were very similar to those observed in style="fixed-case">EMT in style="fixed-case">HCC38 cells. Consequently, we propose style="fixed-case">HCC38 as a suitable model to analyze style="fixed-case">EMT– style="fixed-case">MET dynamics that could affect the development of triple‐negative breast cancer.