Disruption of the Circadian Clock drives Apc Loss of Heterozygosity to Accelerate Colorectal Cancer

Colorectal tumors harbor driver mutations in Apc that lead to adenoma development, however, additional mutations drive progression to adenocarcinoma. Our data demonstrate that genetic disruption of the circadian clock acts synergistically with Apc mutation to accelerate colorectal cancer (CRC) progression. Using an intestinal organoid model, we demonstrate that clock disruption accelerates transformation by driving Apc loss of heterozygosity (LOH), which results in hyperactivation of Wnt signaling. Transcriptomic and metabolomic analyses of transformed organoids reveal a shift towards heightened glycolytic metabolism through c-Myc, a known Wnt-target. Real-time bioluminescence monitoring of the clock in patient-derived organoids (PDOs) demonstrates that circadian rhythms are lost in tumor versus normal colon PDOs. Consistent with mouse and organoid models, we find that concordance of core clock and Wnt pathway genes is sufficient to significantly predict CRC patient survival using data in The Cancer Genome Atlas (TCGA ). Our findings demonstrate that circadian clock disruption drives Apc LOH, hyperactivating intestinal Wnt signaling, and accelerating CRC.