Epithelial cell-fate switch triggering ectopic ligand-receptor-mediated JAK-STAT signaling promotes tumorigenesis in Drosophila.

Disruption of epithelial architecture is a hallmark of human malignant cancers, yet whether and how epithelial deformation influences tumor progression has been elusive. Here, through a genetic screen in Drosophila eye disc, we explored mutations that potently promoted Ras-activated (Ras(V12)) tumor growth and identified eyes absent (eya), an eye determination gene, whose mutation compromised tissue growth but synergized with Ras(V12) to cause massive overgrowth. Furthermore, induction of cell-fate switch by mis-expression of Abd-B in the eye disc also induced massive Ras(V12) overgrowth. Mechanistically, cell-fate switch caused epithelial invagination accompanied by partial mislocalization of the transmembrane receptor Domeless (Dome) from the apical to the basal membrane of the eye epithelium, where its ligand Unpaired3 (Upd3) is present. This led to JAK-STAT activation that cooperates with Ras(V12) to drive tumor progression. Our data provide a mechanistic explanation for how cell-fate switch and subsequent epithelial deformation creates a cancer-prone environment in the epithelium.