SUMMARYCell competition is a conserved mechanism that regulates organ size and shares properties with the early stages of cancer. In Drosophila, wing cells with increased Myc or with optimum ribosome function become supercompetitors that kill their wild-type neighbors (called losers) up to several cell diameters away. Here, we report that modulating STAT activity levels regulates competitor status. Cells lacking STAT become losers that are killed by neighboring wild-type cells. By contrast, cells with hyper-activated STAT become supercompetitors that kill losers located at a distance in a manner that is dependent on hid but independent of Myc, Yorkie, Wingless signaling, and of ribosome biogenesis. These results indicate that STAT, Wingless and Myc are major parallel regulators of cell competition, which may converge on signals that non-autonomously kill losers. As hyper-activated STATs are causal to tumorigenesis and stem cell niche occupancy, our results have therapeutic implications for cancer and regenerative medicine.

In response to varying stress signals, the p53 tumor suppressor is able to promote repair, survival, or elimination of damaged cells - processes that have great relevance to organismal aging. Although the link between p53 and cancer is well established, the contribution of p53 to the aging process is less clear. Delineating how p53 regulates distinct aging hallmarks such as cellular senescence, genomic instability, mitochondrial dysfunction, and altered metabolic pathways will be critical. Mouse models have further revealed the centrality and complexity of the p53 network in aging processes. While naturally aged mice have linked longevity with declining p53 function, some accelerated aging mice present with chronic p53 activation, whose phenotypes can be rescued upon p53 deficiency. Further, direct modulation of the p53-MDM2 axis has correlated elevated p53 activity with either early aging or with delayed-onset aging. We speculate that p53-mediated aging phenotypes in these mice must have (1) stably active p53 due to MDM2 dysregulation or chronic stress or (2) shifted p53 outcomes. Pinpointing which p53 stressors, modifications, and outcomes drive aging processes will provide further insights into our understanding of the human aging process and could have implications for both cancer and aging therapeutics.

Summary In growing tissues, cell fitness disparities provoke interactions that promote stronger cells at the expense of the weaker in a process called cell competition. The mechanistic definition of cell fitness remains unclear, as does how differences are recognized. In Drosophila cells with extra Myc activity acquire “super-competitor” status upon confrontation with wild-type (WT) cells, prompting the latters’ elimination via apoptosis. Confrontation enhances Myc cell fitness by increasing glycolytic flux and promoting expansion of the population. p53 is induced in these cells and promotes their enhanced metabolism. Whereas p53 loss in noncompeting Myc cells is inconsequential, it impairs metabolism, reduces viability and prevents the killing activity of Myc super-competitor cells. We propose that p53 acts as a general sensor of competitive confrontation to enhance the fitness of “winner” cells. Our findings suggest that the initial confrontation between pre-cancerous and WT cells could enhance cancer cell fitness and promote tumor progression.

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Generation of an organ of appropriate size and shape requires mechanisms that coordinate growth and patterning, but how this is achieved is not understood. Here we examine the role of the growth regulator dMyc in this process during Drosophila wing imaginal disc development. We find that dMyc is expressed in a dynamic pattern that correlates with fate specification of different regions of the wing disc, leading us to hypothesize that dMyc expression in each region directs its growth. Consistent with this view, clonal analysis of growth in each region demonstrated distinct temporal requirements for dMyc that match its expression. Surprisingly, however, experiments in which dMyc expression is manipulated reveal that the endogenous pattern has only a minor influence on wing shape. Indeed, when dMyc function is completely lacking in the wing disc over most of its development, the discs grow slowly and are small in size but appear morphologically normal. Our experiments indicate, therefore, that rather than directly influence differential growth in the wing disc, the pattern of dMyc expression augments growth directed by other regulators. Overall, however, an appropriate level of dMyc expression in the wing disc is necessary for each region to achieve a proportionately correct size.H OW pattern and growth are coordinated during development to produce an organ of correct size and shape is a central question in biology. The Drosophila wing is an elegant, self-organizing system that is ideal for the study of this coordination. Wing growth is coupled to the specification of cell fates, and these processes are regulated by a small number of conserved signaling pathways and selector proteins. The wing develops from the wing imaginal disc, a proliferating epithelium housed in the larva that also gives rise to the dorsal thorax of the adult fly. The adult wing includes the blade, made from wing pouch (WP) cells of the wing disc, and hinge structures, which are formed by cells immediately proximal to the WP.Wing development proceeds through a series of steps in which regions of fates are specified. Discs begin development composed of cells with either anterior (A) or posterior (P) identity and subsequently undergo several subdivisions. Early in the second larval instar (L2), the action of Wingless (Wg) and the EGF receptor divide the wing disc into large domains that define the body wall and wing (Wang et al. 2000;Zecca and Struhl 2002).