Induction of entosis by epithelial cadherin expression

Abstract

Cell engulfment typically targets dead or dying cells for clearance from metazoan tissues. However, recent evidence demonstrates that live cells can also be targeted and that engulfment can cause cell death. Entosis is one mechanism proposed to mediate the engulfment and killing of live tumor cells by their neighbors, an activity often referred to as cell cannibalism. Here we report that the expression of exogenous epithelial cadherin proteins (E-or P-cadherin) in human breast tumor cells lacking endogenous expression of epithelial cadherins induces entosis and inhibits transformed growth. Entosis induced by cadherin expression is associated with the polarized distribution of Rho and Rho-kinase (ROCK) activity within entotic cells, which is dependent on p190A RhoGAP activity. ROCK inhibition or downregulation of p190A RhoGAP expression reduces entosis and increases the transformed growth of epithelial cadherin-expressing tumor cells. These data define new cell systems for the study of entosis, and identify entosis as a mechanism of cell cannibalism that is induced by the establishment of epithelial adhesion and inhibits transformed growth.

Entosis, a key player in cancer cell competition

“…The first paper of this series [5] provides evidence that one of the most prominent oncogenes, activated Kras, can stimulate entosis, while the second paper [6] demonstrates that a prominent tumor suppressor, epithelial cadherin (E-cadherin), can increase entosis as well.…”

“…Two papers by Sun et al [5,6] recently published in Cell Research characterized one particular mechanism of homotypic live cell engulfment termed entosis. The first paper of this series [5] provides evidence that one of the most prominent oncogenes, activated Kras, can stimulate entosis, while the second paper [6] demonstrates that a prominent tumor suppressor, epithelial cadherin (E-cadherin), can increase entosis as well.…”

Implication of cell-in-cell structures in the transmission of HIV to epithelial cells

“…Recently, a similar phenomenon was discovered in the development of lower organisms, such as C. elegans [12], suggesting that cell-in-cell structure formation is evolutionarily conserved. Moreover, the formation of homotypic cell-in-cell structure by entosis may mediate competition among tumor cells and thus promote clonal selection and tumor evolution [13][14][15]. Our work on HIV and EBV identifies a novel function of cell-in-cell structure formation.…”

Engineering Whole Mammalian Cells for Target‐Cell‐Specific Invasion/Fusion

“…Natural cell invasion is reported to require polarized actin dynamics in the invader cells 4, 5. More concretely, in an invader cell, RhoA deactivator (e.g., a GTPase‐activating protein for Rho, p190A RhoGAP) accumulates at the cell–cell interface with a receiver cell,5 and RhoA activator (e.g., a guanine nucleotide exchange factor (GEF) for Rho, PDZ‐RhoGEF) accumulates at the rear side of the invader cell 4.…”

“…More concretely, in an invader cell, RhoA deactivator (e.g., a GTPase‐activating protein for Rho, p190A RhoGAP) accumulates at the cell–cell interface with a receiver cell,5 and RhoA activator (e.g., a guanine nucleotide exchange factor (GEF) for Rho, PDZ‐RhoGEF) accumulates at the rear side of the invader cell 4. We hypothesized that this polarization of RhoA activity, inside the invader‐cell‐to‐be, is sufficient to cause cell invasion, and thought about how to synthetically induce this polarization in response to specific cell contact.…”