Cell Competition Drives the Formation of Metastatic Tumors in a Drosophila Model of Epithelial Tumor Formation

Abstract

Cell competition is a homeostatic process in which proliferating cells compete for survival. Elimination of otherwise normal healthy cells through competition is important during development and has recently been shown to contribute to maintaining tissue health during organismal aging. The mechanisms that allow for ongoing cell competition during adult life could, in principle, contribute to tumorigenesis. However, direct evidence supporting this hypothesis has been lacking. Here, we provide evidence that cell competition drives tumor formation in a Drosophila model of epithelial cancer. Cells expressing EGFR together with the conserved microRNA miR-8 acquire the properties of supercompetitors. Neoplastic transformation and metastasis depend on the ability of these cells to induce apoptosis and engulf nearby cells. miR-8 expression causes genome instability by downregulating expression of the Septin family protein Peanut. Cytokinesis failure due to downregulation of Peanut is required for tumorigenesis. This study provides evidence that the cellular mechanisms that drive cell competition during normal tissue growth can be co-opted to drive tumor formation and metastasis. Analogous mechanisms for cytokinesis failure may lead to polyploid intermediates in tumorigenesis in mammalian cancer models.

The role of tumour heterogeneity and clonal cooperativity in metastasis, immune evasion and clinical outcome

“…Eichenlaub et al [61] used a D. melanogaster model of epithelial tumour formation to show that overexpression of both epidermal growth factor receptor (EGFR) and miR-8 in wing imaginal disc cells results in supercompetitive cells that engulf those surrounding them. These supercompetitive cells drive tumourigenesis and metastasis, whereas cells overexpressing either EGFR or miR-8 alone do not.…”

Survival of the Fittest: Essential Roles of Cell Competition in Development, Aging, and Cancer

“…In this context, supercompetitor mutations may act like 'driver' mutations, which provide a slight competitive advantage to a clonal population within the tumor [93] ( Figure 4C). Recently it was shown that competition within clones/domains overexpressing EGFR and the microRNA mir8 was required for metastasis in the fly imaginal disc [94]. In this situation, the spontaneous variability of downstream effectors between clonal cells (e.g., Myc levels) is probably driving competition.…”

“…Similarly, cell competition may also occur within the tumor in mammals as a result of spontaneous variability of protein levels and/or the diversity of genetic background. The elimination of the less-competitive cells may promote the expansion of drug-resistant subpopulations during cancer treatment [88] or the selection of invasive populations [94].…”

Mechanisms of cell competition emerging from Drosophila studies

“…The overgrowing EGFR+miR8 clones induce cell death in nearby wild type cells. However, EGFR+mir8 clones cannot expand through cells that have higher Myc levels, showing that these tumors are susceptible to suppression by competition, and might use competition themselves to expand through wild type cells [47]. …”