A whole-genome screen identifies a bilateral Flower-Grindelwald/TNFR-Veli/LIN-7 communication module in cell competition

<jats:p> Viable yet suboptimal (″loser″) cells can be recognized and selectively eliminated when in the presence of neighboring fitter (″winner″) cells through cell competition, thereby promoting optimal tissue fitness and homeostasis. One mechanism through which cells compare their relative fitness levels relies on isoforms of the conserved transmembrane protein Flower (Fwe). Despite the role of Fwe-dependent cell selection in several pathophysiological processes, little is known about downstream components of this pathway. In this study, we develop a versatile clonal interaction assay in <jats:italic>Drosophila</jats:italic> , the Easy Win Assay. By overexpressing human FWE1 Lose isoform to trigger cell competition, we perform an unbiased whole-genome RNAi screen and identify new pathway modulators. We show that the receptor Grindelwald/TNFR is necessary in either winner or loser cells to drive Eiger/TNF-α-independent elimination of losers, whereas the scaffolding protein Veli/LIN-7 is simultaneously required in both cell populations. We further demonstrate that Fwe, Grindelwald and Veli redistribute to establish a previously undescribed bilateral communication module at winner-loser interfaces, promoting intercellular communication and elimination of loser cells. These findings show that distinct cell elimination pathways converge on a common execution module while remaining independently regulated upstream, enabling flexible recognition and elimination of diverse damaged or dangerous cells. </jats:p>