Impaired formation of homotypic cell-in-cell structures in human tumor cells lacking alpha-catenin expression

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.

Mechanisms and consequences of entosis

“…The entosis engulfment mechanism, unlike phagocytosis, involves epithelial adherens junctions, composed of the cell-cell adhesion receptor E-cadherin and the adherens junction/cytoskeleton linker protein α-catenin, which are necessary (Overholtzer et al 2007; Wang et al 2015), and sufficient (Sun et al 2014a; Wang et al 2015), to mediate entosis in breast tumor cell populations. Entotic cells, unlike cells engulfed by phagocytosis, also play an active role in controlling their own uptake through RhoA-GTPase activity and the RhoA effector kinases Rho-kinases I and II (ROCKI/II) (Figure 1) (Overholtzer et al 2007).…”

Mesenchymal stem cells generate distinct functional hybrids in vitro via cell fusion or entosis

“…Entosis occurs when a living cell invade another cell’s cytoplasm caused by the detachment from the extracellular matrix (ECM)41424344. To further investigate the two observed phenotypes, we analysed eGFP + /mRFP + -sorted cells by time-lapse microscopy.…”

“…Entosis requires active actin polymerization, myosin II contraction and the activity of the Rho signalling pathway414243444546. To investigate whether cell fusion requires the same machinery, mixed cells were treated either with cytochalasin D (cytD), an inhibitor of actin polymerization, or with the myosin II inhibitor blebbistatin.…”

“…Entosis is a form of cell-in-cell structure originated by the active invasion of one living cell into another. It is caused by the loss of cell-matrix adhesion and it is mediated by adherent junctions and by the activity of the Rho-ROCK-actin/myosin pathways414243444546.…”

Macrophages are involved in cell-in-cell structures in human tumors

“…CICs are divided into homotypic CICs and heterotypic CICs according to the referred cell types [4,12] . Formation of homotypic CICs between cells of the same types, usually by entosis, requires cadherin-mediated cell-cell adhesion [6,13] and the activation of the Rho-ROCK-myosin II pathway [7,14] , which may mediate competition among human tumor cells and thus promote clonal selection and tumor evolution [7,15,16] . The heterotypic cell-in-cell interactions, which have often been referred to as emperipolesis, can occur between host and target cells of diverse cell types [17] and play roles in both physiological and pathological processes.…”