Abstract
Although cell-in-cell structures (CICs) could be detected in a wide range of human tumors, homotypic CICs formed between tumor cells occur at low rate for most of them. We recently reported that tumor cells lacking expression of E- and P-cadherin were incapable of forming homotypic CICs by entosis, and re-expression of E- or P-cadherin was sufficient to induce CICs formation in these tumor cells. In this work, we found that homotypic CICs formation was impaired in some tumor cells expressing high level of E-cadherin due to loss expression of alpha-catenin (α-catenin), a molecular linker between cadherin-mediated adherens junctions and F-actin. Expression of α-catenin in these tumor cells restored cell-cell adhesion and promoted CICs formation in a ROCK kinase-dependent way. Thus, our work identified α-catenin as another molecule in addition to E- and P-cadherin that were targeted to inactivate homotypic CICs formation in human tumor cells.
Highlights
Are rather complex than initially described, and could be classified into homotypic or heterotypic cell-in-cell structures (CICs) based on the cells involved[10,11]
E-cadherin levels in ZR75-1, H820 and H441 cells are even higher than that in MCF10A and MCF7, two cells show high level of CICs formation upon induction (Fig. 1B), which suggests that mechanisms other than loss of epithelial cadherins should be responsible for defects in CICs formation in these cells
Being extensively reported in human tumors for a long time, the mechanisms underlying CICs formation remained unexplored until recent years, when several research models were established[8,12,13]
Summary
Are rather complex than initially described, and could be classified into homotypic or heterotypic CICs based on the cells involved[10,11]. Heterotypic CICs are usually formed by penetration of lymphocytes into tumor cells through processes like emperitosis[12]. Mechanisms like entosis and homotypic cell cannibalism (HoCC) are responsible for this type of CICs formation[8,13]. Tumor cells lacking epithelial cadherins (Eand P-cadherin) failed to form CICs, re-expression of E- or P-cadherin could efficiently induce CICs in these cells, suggesting that disrupting AJs is a mechanism whereby tumor cells escape entosis-mediated CICs formation[9]. We found that tumor cells deficient of α -catenin, a key component of functional AJs, displayed impaired CICs formation, which could be fixed by restored expression of α -catenin. Tumor cells could escape entotic CICs formation by targeting multiple AJs components including E-/P-cadherin and α -catenin, and CICs formation by entosis may constitute a novel mechanism underlying the tumor suppressive function imposed by α -catenin
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