Dynamic cellular interactions occur between heterogeneous cell populations during both development and tumorigenesis. Intricate cellular communication also underpins ‘cell competition’, a conserved tumor-suppression mechanism whereby aberrant “loser” cells are actively eliminated by neighboring “winner” cells. For example, while Drosophila tissue mutant for conserved apicobasal-polarity gene scribble (scrib) forms lethal neoplasms, mosaic clones of scrib cells are eliminated by neighboring wild-type cells. While cell competition is conserved in vertebrates and can similarly function as a tumor-suppressor, the mechanisms underlying how cell competition enforces homeostasis remain incompletely understood.
To gain insight into cell competition, we conducted a genetic deficiency screen in Drosophila eye epithelia mosaic for scrib and wild-type cells. We identified the axon-guidance signaling system, Slit-Roundabout (Robo), as essential for proper scrib cell elimination. Heterozygosity for the secreted ligand slit or the transmembrane receptors robo1 or robo2, but not robo3, caused aberrant scrib clone overgrowth. Moreover, Slit-Robo antibodies accumulated around specific populations of apically extruding scrib cells. Through genetic perturbation of Slit-Robo within or around scrib clones, we demonstrate that Slit acts locally on Robos inside scrib cells to extrude the aberrant loser cells away from the main epithelium. One source of the Slit ligand required for scrib cell competition is scrib loser cells, suggesting that Slit-Robo signaling is autocrine in the context of scrib competition.
Surprisingly, while Robo-overexpression in scrib cells drastically enhanced apical extrusion of scrib clones, it also unexpectedly blocked scrib cell elimination. Instead, excessive extrusion merged scrib clones in the apical lumen and prevented proper cell competition. Thus, balanced Slit-Robo signaling and extrusion are essential for scrib cell competition and homeostasis. Notably, either loss or gain of Slit-Robo signaling is associated with various human epithelial cancers. Because cell competition also eliminates human cell lines mutant for scrib, epithelial Slit-Robo signaling could broadly enforce tumor-suppression and epithelial homeostasis through the removal of aberrant, precancerous loser cells.