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The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c−/−) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated with increased spontaneous and carcinogen-induced systemic tumorigenesis in Gucy2c−/− mice. GUCY2C regulated barrier integrity by repressing AKT1, associated with increased junction proteins occludin and claudin 4 in mice and Caco2 cells in vitro. Thus, GUCY2C defends the intestinal barrier, opposing colitis and systemic genotoxicity and tumorigenesis. The therapeutic potential of this observation is underscored by the emerging clinical development of oral GUCY2C ligands, which can be used for chemoprophylaxis in inflammatory bowel disease and cancer.

An evolving paradigm expanding the genetic basis of cancer suggests that tissue-specific developmental programs indelibly imprint restricted repertoires governing homeostasis, forming the substrate for lineage-dependent tumor induction by dysregulation of survival pathways. GUCY2C, the intestinal receptor for the paracrine hormones guanylin and uroguanylin whose early loss characterizes transformation, has emerged as a component of developmental programs organizing spatiotemporal patterning along the crypt-surface axis whose dysregulation promotes hyperproliferation and genetic instability underlying neoplasia. Here we identify GUCY2C as a reversible switch for lineage-dependent tumorigenesis whose disruption amplifies survival circuits essential for regenerative homeostasis and required for transformation. Elimination of GUCY2C in mice expands proliferating crypts, accelerating the cell cycle at the G1/S transition. Proliferative induction is coupled with altered metabolic programming, with an increase in aerobic glycolysis and a reciprocal reduction in mitochondrial biogenesis and oxidative phosphorylation, recapitulating the metabolic phenotype of human tumors. Conversely, GUCY2C signaling restores homeostatic circuits in colon cancer cells, decelerating the cell cycle and switching ATP production from glycolysis to mitochondrial metabolism, recapitulating normal enterocytes. Moreover, oral administration of the downstream mediator of GUCY2C signaling, cyclic GMP, reverses crypt hyperplasia and restores normal proliferative and metabolic programs in mice deficient in GUCY2C. Coordination of survival circuits by GUCY2C is orchestrated through the oncogene AKT, whose inhibition mimics, and activation eliminates, GUCY2C regulation of proliferation and metabolism. Modulation of AKT signaling by GUCY2C is, in part, mediated by the tumor suppressor, PTEN. Silencing PTEN eliminates GUCY2C regulation of AKT, proliferation and metabolism. Thus, disruption of developmental