Loss of polarity by Cdc42 depletion and oncogenic Kras activation in the mouse intestinal epithelia leads to a necrotizing enterocolitis (NEC)-like disease.

Cell polarity is essential for maintaining intestinal epithelial organization and function. Here we show that combined loss of polarity by epithelial loss of Cdc42 with oncogenic Kras expression in mice causes small intestine failure leading to weight loss, inflammation, epithelial necroptosis, and lethality. These phenotypic defects are characterized by a loss of intestinal stem cells, disrupted epithelial architecture, altered hippo signaling, elevated inflammatory cytokines, and activation of necroptotic cell death, that closely resemble necrotizing enterocolitis (NEC). Single-cell transcriptomic analysis reveals a coordinated dysregulation of polarity machinery, inflammatory pathways, and necroptosis program. Suppression of YAP, IL-1, TNFα signaling or necroptosis rescues the intestinal pathology. Similar NEC-like phenotypes arise when Cdc42 loss and oncogenic Kras activation are initiated from intestinal stem cells. These findings provide mechanism insights involving polarity-YAP-IL1/TNFα signaling induced necroptosis for the synergistic effect of hyperactivation of Kras signaling and loss of polarity in disrupting intestinal epithelia.