Membrane depolarization drives tumor-suppressive cell competition via hedgehog signaling activation

Tumor-suppressive cell competition (TSCC) is an evolutionarily conserved process that safeguards tissue integrity by selectively eliminating less-fit, precancerous cells. While bioelectric regulation via plasma membrane potential (V_m) is emerging as a key modulator of cellular fitness, its mechanistic role in TSCC remains underexplored. Here, we combine Drosophila genetics, single-cell RNA sequencing (scRNA-seq), and mammalian co-culture models to indicate that V_m depolarization acts as a critical driver of TSCC through Hedgehog (Hh) signaling. In Drosophila eye epithelia, scribble-deficient (scrib^-/-) "loser" clones exhibit mitochondrial respiratory chain defects, leading to reduced ATP synthesis and subsequent plasma membrane depolarization. This depolarization stabilizes Smoothened at the membrane, aberrantly activating Hedgehog signaling and triggering the elimination of scrib^-/- clones. Notably, we observe a striking mechanistic parallel in mammalian epithelia: Scrib-depleted Madin-Darby Canine Kidney (MDCK) cells similarly undergo V_m depolarization-dependent elimination associated with Hh pathway activation. Together, our work advances the understanding of bioelectricity in cancer surveillance and suggests that targeting membrane potential could offer a promising therapeutic strategy for cancer prevention by exploiting cell competition mechanisms.