Abstract SY29-03: Competition between tumor cells by entosis
Authors: Sun Qiang , Luo Tianzhi , Ren Yixin , Florey Oliver , Cibas Edmund S. , Hodgson Louis , Robinson Douglas N. , Overholtzer Michael 
Published: May 2015

Cell engulfment mechanisms maintain metazoan tissue homeostasis by removing dying cells and pathogenic organisms. But recent evidence suggests that engulfment mechanisms also target viable cells and could therefore regulate rates of physiologic cell turnover in some contexts. One mechanism that targets live cells for engulfment is called entosis.

By entosis, human tumor cells use the machinery of cell-cell adhesion to ingest their live neighbors, in a manner dependent on Rho-GTPase signaling and actomyosin. Live cells ingested by entosis are killed in a non-cell-autonomous manner by engulfing cells, following modification of entotic vacuoles by autophagy pathway proteins and lysosome fusion. We have shown that this mechanism of entotic cell death can limit transformed growth, suggesting a potential mechanism of tumor suppression linked to the engulfment and killing of live cells. Alternatively, we have shown that engulfing cells recover nutrients from ingested cells, and that entosis promotes the development of aneuploidy, suggesting that this process could promote tumor progression. Consistent with this, cell structures resembling those formed by entosis are observed most frequently in high-grade breast tumors that exhibit high rates of aneuploidy and aggressive clinical characteristics.

Here we investigate the mechanism of entosis and consider that engulfments between neighboring viable cells could promote a form of cell competition, where “winner” cells engulf and kill neighboring “losers”. We find that differences in cortical mechanics (specifically, cortical deformability, which reflects the apparent elastic modulus and cortical tension) between neighboring cells, mediated by the Rho-GTPase pathway, dictate winner versus loser cell status, and that epithelial cadherin (E- and P-cadherin) expression is sufficient to induce this mode of competition between tumor cells. Tumor cells with high deformability preferentially engulf and outcompete neighboring cells with low deformability in heterogeneous populations. We further find that activated Kras and Rac signaling impart winner status to cells by downregulating contractile myosin, allowing for the internalization of neighboring cells that undergo cell death.

These data define a mechanism of competition between mammalian cells that occurs in human tumors. Human tumors are known to be genetically heterogeneous, with many tumors exhibiting multiple independent clones identified by genetic alterations such as changes in ploidy. Entosis could allow neighboring cells to compete by acting as a mechanism of cell death toward losers, while selecting for more deformable winners and endowing them with ploidy changes and nutrient advantages that promote tumorigenesis. Our data add to an expanding list of mammalian cell competition mechanisms by demonstrating a mode of direct competition that utilizes cell engulfment, which is dependent on cell adhesion and differential cell mechanics, to allow winners to kill losers.

Citation Format: Qiang Sun, Tianzhi Luo, Yixin Ren, Oliver Florey, Edmund S. Cibas, Louis Hodgson, Douglas N. Robinson, Michael Overholtzer. Competition between tumor cells by entosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY29-03. doi:10.1158/1538-7445.AM2014-SY29-03