Carcinoma cells induce lumen filling and EMT in epithelial cells by soluble E-cadherin-mediated activation of EGFR

In epithelial cancers, carcinoma cells coexist with normal cells. While it is known that the tumor microenvironment (TME) plays a pivotal role in cancer progression it is not completely understood how the tumor influences adjacent normal epithelial cells. In this study, a 3D co-culture system comprising of non-transformed epithelial cells (MDCK) and transformed carcinoma cells (MSV-MDCK) was used to demonstrate that carcinoma cells sequentially induced preneoplastic lumen filling and EMT in epithelial cysts. MMP-9 secreted by carcinoma cells cleaves cellular E-cadherin from epithelial cells to generate soluble E-cadherin (sE-cad), a pro-oncogenic protein. We show that sE-cad induces EGFR activation resulting in lumen filling in MDCK cysts. Long-term sE-cad treatment induced EMT. sE-cad caused lumen filling by induction of the ERK signaling pathway, whereas EMT by the sustained activation of AKT pathway. While it is known that sE-cad induces MMP-9 release and consequent EGFR activation in tumor cells, our results for the first time demonstrate that carcinoma cells can induce sE-cad shedding in adjacent epithelial cells which leads to EGFR activation and the eventual transdifferentiation of the normal epithelial cells.