Competition between human cells by entosis

Abstract

Human carcinomas are comprised of complex mixtures of tumor cells that are known to compete indirectly for nutrients and growth factors. Whether tumor cells could also compete directly, for example by elimination of rivals, is not known. Here we show that human cells can directly compete by a mechanism of engulfment called entosis. By entosis, cells are engulfed, or cannibalized while alive, and subsequently undergo cell death. We find that the identity of engulfing ("winner") and engulfed ("loser") cells is dictated by mechanical deformability controlled by RhoA and actomyosin, where 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 eventually undergo cell death. Finally, we compute the energy landscape of cell-in-cell formation, demonstrating that a mechanical differential between winner and loser cells is required for entosis to proceed. These data define a mechanism of competition in mammalian cells that occurs in human tumors.

Entosis, a key player in cancer cell competition

“…One particular type of competition among distinct cells may consist in the engulfment of one cell (the 'loser') by another (the 'winner'), as demonstrated by Sun et al in several cell culture models, as well as in human cancers that were xenografted into immunodeficient mice [5]. Importantly, co-culture of non-transformed cells with their malignant counterparts systematically leads to engulfment of the former by the latter, suggesting that oncogenic transformation is coupled to the 'winner' status [5].…”

“…One particular type of competition among distinct cells may consist in the engulfment of one cell (the 'loser') by another (the 'winner'), as demonstrated by Sun et al in several cell culture models, as well as in human cancers that were xenografted into immunodeficient mice [5]. Importantly, co-culture of non-transformed cells with their malignant counterparts systematically leads to engulfment of the former by the latter, suggesting that oncogenic transformation is coupled to the 'winner' status [5]. Indeed, competition by entosis leads to the physical elimination of the 'loser' cells, which usually succumb to non-apoptotic cell death as soon as the phagosome enveloping the engulfed cell is decorated with LC3 and then fuses with lysosomes [1,7].…”

“…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.…”