Mechanisms of cell competition emerging from Drosophila studies

Abstract

Cell competition was described in Drosophila as the loss from mosaic tissues of otherwise viable cells heterozygous for Ribosomal protein mutations ('Minutes'). Cell competition has now been described to occur between multiple other genotypes, such as cells differing in myc expression levels, or mutated for neoplastic tumor suppressors. Recent studies implicate innate immunity components, and possibly mechanical stress, compression and cell intercalation as a consequence of differential growth rates in competitive cell death. Competition to eliminate pre-neoplastic tumors makes use of signals and receptors also used in patterning the nervous system including Slit/Robo2 and Sas/PTP10D to recognize and extrude clones of mutant cells, at least where local epithelial cyto-architecture is favorable. Cell competition facilitates expansion of Drosophila tumors through host tissue, and in normal development may promote developmental robustness and longevity by selecting for optimal progenitor cells.

FIGURE 1. The phenomenon of cell competition

(A) In the classic example of cell competition shown by cells heterozygous for mutations of dose-sensitive Ribosomal protein genes (‘Minute’ cells), these slow-growing cells are actively eliminated from mosaic tissues containing wild type cells [1]. Clones of the ‘Minute’ cells (white) attempt to grow in the presence of normal cells (black), but apoptosis (small cells) progressively removes them [15,16]. Other examples of out-competed cells, including the neoplastic tumor mutants like scrib, are extruded from the epithelium as well as subject to cell death (see Figure 2) (B) In the converse situation, a clone of more competitive cells, for example cells expressing elevated Myc levels (grey), expand within the growing imaginal disc at the expense of surrounding normal cells (black), which are themselves killed (small cells) [5,22]. Not shown in panels (A) and (B) are the mechanical consequences of differential growth in epithelia. Typically, differential growth in mosaics leads to cell crowding and compaction in the vicinity of the faster-growing genotype [23,30*].

FIGURE 2. Tumor-suppressive competition

Clones of cells mutant for neoplastic tumor mutations, exemplified by scrib, are eliminated from mosaic imaginal discs by apoptosis and extrusion, depending on JNK signaling in the mutant cells. JNK is activated by the Drosophila TNF-alpha factor Eiger and its receptor Grindelwald as an autocrine consequence of disrupted polarity or endosomal function [37,40]. Within scrib mutant cells, JNK promotes autocrine activation of Slit/Robo2 signaling [39**]. Slit/Robo2 signaling through Ena downregulates E-cadherin and also affects the cytoskeleton to promote extrusion from the epithelium. This only occurs in mosaic tissues also containing wild type cells, because interaction between Sas in neighboring wild type cells and PTP10D in scrib mutant cells holds EGFR signaling to Ras in check. Without this suppression of EGFR signaling, combined Ras and JNK activity promote tumor growth and survival, not extrusion [41**]. Simultaneously, JNK activity in surrounding wild type cells promotes expression of the PDGF-receptor Pvr, which signals through ELMO and Rac to promote apoptosis and engulfment of the scrib mutant cells [43].