Mesenchymal-transitioned cancer cells instigate the invasion of epithelial cancer cells through secretion of WNT3 and WNT5B.

Although the heterogeneities of epithelial and mesenchymal-transitioned cancer cells are often observed within the tumor microenvironment, the biological significance of the interaction between epithelial cancer cells and mesenchymal-transitioned cancer cells is not yet understood. In this study, we show that the mesenchymal-transitioned cancer cells instigate the invasive ability and metastatic potential of the neighboring epithelial cancer cells in vitro and in vivo. We identify WNT3 and WNT5B as critical factors secreted from Transforming growth factor-induced mesenchymal cancer cells for instigating the epithelial cancer cell invasion along with the induction of secondary EMT phenotype. These results shed light on the significance of cancer heterogeneity and the interaction between epithelial and mesenchymal-transitioned cancer cells within the tumor microenvironment in promoting metastatic disease through the WNT-dependent mechanism.