The Warburg effect is one of the hallmarks of cancer cells, characterized by enhanced aerobic glycolysis. Despite intense research efforts, its functional relevance or biological significance to facilitate tumor progression is still debatable. Hence the question persists when and how the Warburg effect contributes to carcinogenesis. Especially, the role of metabolic changes at a very early stage of tumorigenesis has received relatively little attention, and how aerobic glycolysis impacts tumor incidence remains largely unknown. Here we discuss a novel paradigm for the effect of the Warburg effect that provides a suppressive role in oncogenesis.Key words: Warburg effect, aerobic glycolysis, cell competition, EDAC.

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Normal epithelial cells exert their competitive advantage over RasV12-transformed cells and eliminate them into the apical lumen via cell competition. However, the internal or external factors that compromise cell competition and provoke carcinogenesis remains unknown. In this study, we examined the effect of sequential accumulation of gene mutations, mimicking multi-sequential carcinogenesis on RasV12-induced cell competition in intestinal epithelial tissues. Consequently, we found that directionality of RasV12-cell extrusion in Wnt-activated epithelia is reversed, and transformed cells are delaminated into the basal lamina via non-cell autonomous MMP21 upregulation. Subsequently, diffusively infiltrating, transformed cells develop into highly invasive carcinomas. Elevated production of MMP21 is elicited partly through NF-κB signaling, blockage of which restores apical elimination of RasV12 cells. We further found that the NF-κB-MMP21 axis is significantly bolstered in early colorectal carcinoma in humans. Collectively, this study shows that cells with high mutational burdens exploit cell competition for their benefit by behaving as unfit cells, endowing them with an invasion advantage.