Mechanisms and consequences of entosis

Abstract

Multiple mechanisms have emerged where the engulfment of whole live cells, leading to the formation of what are called 'cell-in-cell' structures, induces cell death. Entosis is one such mechanism that drives cell-in-cell formation during carcinogenesis and development. Curiously, entotic cells participate actively in their own engulfment, by invading into their hosts, and are then killed non-cell-autonomously. Here we review the mechanisms of entosis and entotic cell death and the consequences of entosis on cell populations.

Keywords: Aneuploidy; Autophagy; Cannibalism; Cell competition; Cell-in-cell; Engulfment; Entosis; Entotic cell death; LAP; Phagocytosis.

Fig. 1

Mechanisms of entosis and entotic cell death. Top images: Matrix detachment of adherent cells triggers entosis, involving formation of E-cadherin and α-catenin-mediated cell junctions (green) between host (blue) and internalizing cells (red). RhoA and Rho kinase (ROCK) activity in internalizing cells leads to actomyosin accumulation at the cell cortex, which drives cell-in-cell formation, suggesting an active invasion–like process. Over time, most internalized cells undergo entotic cell death (top right), involving lipidation of the autophagy protein LC3 onto the entotic vacuole (requiring VPS34 and LC3 lipidation machinery (e.g. Atg5)), followed by lysosome fusion and death of internalized cells. Alternatively, some entotic cells undergo apoptosis, particularly when inhibited for macroautophagy, and others are observed to divide inside of their hosts, or to escape and return to the culture (bottom images)

Fig. 2

Consequences of entosis. a Potential anti-tumorigenic effects of entosis involve the killing of internalized tumor cells. b Potential pro-tumorigenic effects of entosis involve the scavenging of nutrients by host cells, as well as ploidy changes that result from failed cytokinesis. c Model of entosis promoting competition between neighboring cells. Differences in deformability between cells can induce entotic cell engulfment in a population, as cells with high mechanical tension (losers, red) internalize into cells with lower mechanical tension (winners, blue) and undergo cell death. One pathway that can influence this competitive mechanism is the Kras pathway, where the activation of Rac1 by Kras reduces RhoA/ROCK-dependent actomyosin contractility and tension, rendering cells with Kras activation winners. Winner cells eliminate losers while becoming polyploid/aneuploid and also scavenging nutrients to support their own proliferation