Competition for Space Is Controlled by Apoptosis-Induced Change of Local Epithelial Topology

During the initial stage of tumor progression, oncogenic cells spread despite spatial confinement imposed by surrounding normal tissue. This spread of oncogenic cells (winners) is thought to be governed by selective killing of surrounding normal cells (losers) through a phenomenon called “cell competition” (i.e., supercompetition). Although the mechanisms underlying loser elimination are increasingly apparent, it is not clear how winner cells selectively occupy the space made available following loser apoptosis. Here, we combined live imaging analyses of two different oncogenic clones (Yki/YAP activation and Ras activation) in the Drosophila epithelium with computer simulation of tissue mechanics to elucidate such a mechanism. Contrary to the previous expectation that cell volume loss after apoptosis of loser cells was simply compensated for by the faster proliferation of winner cells, we found that the lost volume was compensated for by rapid cell expansion of winners. Mechanistically, the rapid winner-dominated cell expansion was driven by apoptosis-induced epithelial junction remodeling, which causes re-connection of local cellular connectivity (cell topology) in a manner that selectively increases winner apical surface area. In silico experiments further confirmed that repetition of loser elimination accelerates tissue-scale winner expansion through topological changes over time. Our proposed mechanism for linking loser death and winner expansion provides a new perspective on how tissue homeostasis disruption can initiate from an oncogenic mutation. [Display omitted] •Rapid cell expansion of oncogenic mutants fills space of normal cell apoptosis•Topological change by directionally biased cell intercalations drives cell expansion•The topological dynamics is verified with in silico and in vivo experiments•Repetitive rapid cell turnover via topological changes accelerates mutant expansion Tsuboi et al. investigate the spatiotemporal evolution of cell turnover during cell competition. Winner cells compensate for the space of losers’ apoptosis by rapid cell expansion through re-connection of local cellular connectivity (topology). This topology dynamics may drive the pathological development initiated from an oncogenic mutation.