Cell competition is a process by which a population of fitter cells (winners) outcompetes neighbouring weaker cells (losers), inducing their elimination by cell death or differentiation. This mechanism has been proposed to a play role in tissue health and turnover and in disease states such as cancer. There are many known mutations, which can induce a loser status, however despite its discovery four decades ago, the molecular properties of cells that earmark them as losers have not been identified.
To identify molecular differences between winner and loser cells we generated and analysed RNAseq data from control (wild-type) cells and from a subset of loser mutations, from Drosophila wing imaginal discs in the absence of cell competition. We focused on two mutations, which are seemingly functionally unrelated, yet share the loser phenotype: Minute (ribosomal) heterozygous mutations and a mutation in mahj (involved in cell polarity and protein degradation). To enrich for genes involved in the loser cell status we focused on the intersection of genes that were differentially expressed in both of these mutants compared to the wild type. This intersection includes genes indicative of a constitutively activated stress response, encompassing JNK, JAK/STAT, p53/DNA damage and oxidative stress response pathways. We then assessed the functions of these pathways in loser cells. While some pathways have an autonomous pro-survival role, we found that others can specifically modulate cell competition. In particular the JAK/STAT signaling pathway, activated by constitutive production of Unpaired ligands from loser cells, is important not only for loser cell proliferation, but also for cell competition, as it is responsible for the overgrowth of winner cells. Thus, winner cell overgrowth does not require winner-loser recognition, but stems directly from excessive availability of proliferative signals.
In summary, loser cells carrying Minute and mahj mutations exhibit a common molecular signature, which involves activation of stress and pro-survival pathways. JAK/STAT signaling autonomously promotes proliferation while, at the same time non-autonomously boosts growth of the competing winner population.