Program Leader: Leonard Augenlicht, Ph.D.
The Biology of Colon Cancer Program utilizes novel mouse models and strain crosses along with dietary interventions to understand genetic and environmental mechanisms that drive risk for and development of intestinal cancer. Several themes cut across many of these models, including inflammation driving genomic instability and altering metabolic pathways associated with tumor development. New mouse models constructed to investigate defective mismatch repair in Lynch Syndrome and MSI colon tumors showed sensitivity to inhibitors of mTOR signaling and triggering of autophagy. The sensitivity to mTOR inhibition was also noted in a new model of colitis associated colon cancer initiated by targeted inactivation of Stat3 signaling to macrophages. A unique dietary model of sporadic colon cancer reflecting the etiology and pattern of long term development that characterizes human sporadic colon cancer showed an early inflammatory response in the intestinal mucosa as well as in adipocytes, genetic damage in colonic crypts, and was characterized metabolically by increased utilization of lipid as an energy source, development of glucose intolerance, and a shift of colon epithelial cells towards glycolysis long before tumors develop. A novel methodology was developed for whole-genome analysis of single cells using massively parallel sequencing to quantify and identify the spectrum of locus specific somatic mutations that develop in these models as a function of major risk factors for human colon cancer, including genetic predisposition, diet and age. These experiments are focusing on intestinal stem cell populations that are the targets for tumor initiation. New methodologies and mouse models also established haploinsufficiency of the Apc gene in mucosal homeostasis, with inheritance of a single mutant Apc allele attenuating cell maturation along the crypt-luminal axis and shifting cell allocation towards secretory cell lineages, the latter also found to characterize the mucosa at dietary risk for sporadic colon cancer. Forced secretory cell hyperplasia by inhibition of signaling through Notch receptors was achieved by targeting inactivation of the glycosyltransferase Pofut1. This altered the intestinal microbiome, caused significant colitis, and development of dysplasia and tumors, thus revealing a potential complication of targeting Notch signaling as a therapeutic approach. Translational accomplishments included: modulation of intestinal stem cell function by R-spondin for radioprotection of the colonic mucosa; discovery that activation of the pregnane-X receptor altered intestinal tumor cell proliferation, progression and response to chemotherapeutics; application of novel in situ transcription site imaging in single cells for prediction of drug sensitivity of colon tumor cells; identification of signaling components down-stream of ras that define chemoresistant tumors, and investigation of reolysin (reovirus infection) as an alternative therapy for drug resistant mutant ras tumors which included clinical trials.
Selected Achievements of the Biology of Colon Cancer program