Cell competition: how to eliminate your neighbours

Abstract

A conventional view of development is that cells cooperate to build an organism. However, based on studies of Drosophila, it has been known for years that viable cells can be eliminated by their neighbours through a process termed cell competition. New studies in mammals have revealed that this process is universal and that many factors and mechanisms are conserved. During cell competition, cells with lower translation rates or those with lower levels of proteins involved in signal transduction, polarity and cellular growth can survive in a homogenous environment but are killed when surrounded by cells of higher fitness. Here, we discuss recent advances in the field as well as the mechanistic steps involved in this phenomenon, which have shed light on how and why cell competition exists in developing and adult organisms.

Keywords: Apoptosis; Losers; Minute; Myc; Super-competition; Winners.

Fig. 1.

Cell competition. (A) When in a homotypic environment, the cells of two genotypes are viable and produce normal tissues. Blue cells (top) represent less fit cells and green cells (bottom) represent wild-type cells. (B) When these different cells are present in the same tissue (i.e. in a heterotypic environment) competitive interactions take place between them. The less fit cells (blue) are eliminated by apoptosis (dark blue cells), extruded basally (arrows) from the epithelium, and replaced by cells of the fitter type (green). Eventually, the whole compartment (the boundaries of which are indicated by black dashed lines), is colonised by the fitter cell type (green cells). (C) In the case of super-competition, super-competitors (orange) are able to outcompete wild-type cells (green). A clone of super-competitors (orange) induces apoptosis (dark green) and basal extrusion (arrows) of surrounding wild-type cells located up to eight cell diameters away. The subsequent proliferation of super-competitors replaces the outcompeted wild-type cells, resulting in their increased contribution to the final tissue.

Fig. 2.

Potential models of competitive interactions and death. (A) In the ligand capture model, winners (green) capture more survival factor (orange circles) and deprive losers (blue) of it. The lack of a survival signal causes cells to die. (B) In the comparative fitness model, cells sense differences between themselves, leading to competitive interactions. This process can be divided into three sequential steps: sensing differences (step 1), acquisition of status (step 2) and elimination of losers (step 3). Briefly, winners (green) kill losers (light blue) and the dying losers (dark blue) are engulfed by winners and/or are basally extruded and phagocytosed by circulating macrophages (arrow). In step 1, differences in fitness are sensed across a field of naïve epithelial cells (beige) that contains cells of variable fitness. For simplicity, we have drawn a hypothetical surface sensor protein (black). Although many scenarios can be imagined, we propose that the sensor makes homotypic interactions between neighbouring cells (indicated by interlocking black shapes). If cells are different, these interactions may not occur, causing the sensor to become activated (orange, shown here in presumptive winner cells). When this receptor is activated, competitive interactions are induced. In step 2, cells acquire winner (green) or loser (blue) status and begin to express markers of their status. For example, Fwe isoforms (magenta) begin to be expressed in losers. Note that, although no markers of winners have been identified, there is evidence that winners know their status (Senoo-Matsuda and Johnston, 2007). In step 3, extracellular death signals (red) induce death in losers. We do not distinguish between winners producing the death signal that kills losers and losers producing the death signal, resulting in cellular suicide. Ultimately, this competitive stress leads to Hid expression and JNK activation in losers, resulting in apoptosis. Winners themselves might also phagocytose losers and cause their death, via the activation of several phagocytosis proteins downstream of JNK activation.