Polyploidy reprograms epithelial cells for motility and phagocytosis via stress signaling

Polyploidy, an increase in cellular genome content, is a conserved developmental program and a hallmark of malignant cancer, yet its impact on cell behavior remains poorly understood. Here, we show that induction of polyploidy in otherwise diploid cells causes intrinsic stress that reprograms cellular physiology to promote motility-like and phagocytic behaviors. Using the Drosophila wing imaginal disc, we find that induced polyploidy enhances membrane dynamics and triggers dynamic cell behavior through a ROS–JNK stress axis activated by ER stress. These cells also acquire phagocytic activity, engulfing both dead and live neighboring cells in developmental and tumor contexts. This stress-induced reprogramming is conserved in induced poly-aneuploid mammalian cancer cells, linking increased genomic content to metastatic traits. Our findings uncover a conserved role for induced polyploidy in driving stress-responsive and immune cell–like behaviors, revealing how elevated ploidy can reshape epithelial function during development and disease.