Iro-C/IRX creates anti-cancerized epithelial field against IL-6-dependent malignant tumorigenesis

Some epithelial regions appear intrinsically resistant to malignancy, yet how such anti-cancerized fields are established remains elusive. Here, we show in Drosophila that Iroquois Complex (Iro-C), a group of transcriptional repressors specifically expressed in the notum region of the wing imaginal epithelium, creates anti-cancerized field against malignant tumorigenesis. Clones of cells with Ras activation and cell polarity defect (RasV12/scrib-/-) develop into malignant tumors in the pouch and hinge regions of the wing disc, yet they failed to overgrow in the notum. Mechanistically, intrinsic Iro-C expression in the notum represses upd/IL-6 transcription, thereby preventing JAK-STAT activation essential for driving malignant growth. Forced expression of Upd/IL-6 converted the notum into tumor-prone field, whereas forced expression of Iro-C in the pouch and hinge abolished their RasV12/scrib-/- tumorigenesis. Our findings provide a mechanistic explanation for how some epithelial regions, such as distal segments of the kidney, where Iro-C/IRX1 is specifically expressed, exhibit resistance to cancer development, and offer a novel therapeutic strategy against IL-6-dependent cancers.