Oncogenic cells evade cell competition and evolve into tumors through clone size-dependent, progressive elevation of Yki activity

Normal epithelial tissues often exert tumor-suppressive effects against newly emerged oncogenic cells. In Drosophila epithelia, clones of oncogenic polarity-deficient cells mutant for scribble ( scrib ) are eliminated by cell competition when surrounded by wild-type cells. Here, we show that the win-lose fate of scrib mutant cells depends on their initial population size. Small scrib -knockdown ( scrib ^KD ) clones are efficiently eliminated from wing imaginal epithelia, whereas larger clones initially behave as losers but later escape elimination and overgrow into tumors. This shift in competitive behavior in large clones is accompanied by a progressive activation of the Hippo pathway effector Yorkie (Yki). To dissect this intriguing growth dynamics, we extend our previously proposed deterministic mathematical model of cell competition to a stochastic framework incorporating experimentally observed sources of variability. The model reproduces the large variability observed in clone growth dynamics. Furthermore, addition of the effect of late-stage, progressive growth acceleration to the mathematical model recapitulated the experimentally observed size-dependent progressive tumorigenesis. Our findings establish the initial size of oncogenic cell population as the key determinant of the win-lose fate and provide a potential mechanism by which oncogenic clones evade cell competition through size-dependent, progressive elevation of Yki activity.