Abstract #4412: GUCY2C establishes lineage dependence in intestinal tumorigenesis through AKT
Authors: Jieru Lin, Adam Snook, Peng Li, Stephanie Schulz, Giovanni Pitari, Scott Waldman
Journal: Cancer Research (2009)

An evolving paradigm expanding the genetic basis of cancer suggests that tissue-specific developmental programs indelibly imprint restricted repertoires of 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 universally characterizes colorectal transformation, has emerged as a component of homeostatic programs organizing spatiotemporal patterning along the crypt-surface axis, and its dysregulation promotes tumorigenesis through hyperproliferation and genetic instability. Here we identify GUCY2C as a switch for lineage-dependent tumorigenesis whose disruption reprograms survival circuits essential for regenerative homeostasis and universally required for tumorigenesis. Eliminating GUCY2C expression in mice expands proliferating crypts, accelerating the cell cycle by regulating mediators of the G1/S transition, including cyclin D1, pRb, and p27. Further, loss of GUCY2C produces an increase in aerobic glycolysis, reflected by elevated glucose transport and lactate production associated with increased expression of rate-limiting glycolytic proteins universally up-regulated in tumors, including glucose transporter I, hexokinase II, phosphofructokinase, and pyruvate kinase. Conversely, there is a reciprocal reduction in mitochondrial biogenesis and oxidative phosphorylation, reflected by a decrease in mitochondrial genome, proteins, and organelles associated with reduced mitochondrial oxygen consumption, dehydrogenase activity and ATP production, recapitulating the tumor metabolic phenotype. Conversely, GUCY2C signaling restores replicative and metabolic homeostatic circuits in colon cancer cells, recapitulating the phenotype of normal enterocytes. Moreover, oral administration of the proximal downstream mediator of GUCY2C, cyclic GMP, reverses crypt hyperplasia and restores 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. AKT modulation by GUCY2C involves the tumor suppressor PTEN, whose silencing eliminates GUCY2C regulation of AKT, proliferation and metabolism. Thus, disruption of developmentally restricted signaling by GUCY2C, reflecting loss of paracrine hormones, induces maladaptive survival pathways essential for crypt-surface homeostasis whose tissue-specific deregulation contributes to lineage dependency in intestinal tumorigenesis. With the role of guanylin and uroguanylin loss in transformation, the universal compensatory over-expression of GUCY2C by colorectal tumors offers a unique therapeutic opportunity for cancer prevention through oral hormone supplementation.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4412.