Delineating the role of the circadian clock in cancer, anti-tumor immunity, and fetal reprogramming
Abstract
The circadian clock is the internal biological pacemaker that regulates critical cellular processes including immunity, metabolism, and cell cycle control. Disruption of the circadian clock has been shown to increase the risk of cancer development and progression; however, the underlying mechanism requires further investigation. Our lab has developed a novel genetically engineered mouse model to study the impact of circadian clock disruption on colorectal cancer. We find that both genetic disruption and environmental disruption of the circadian clock accelerate Apc-driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving Apc loss of heterozygosity and subsequent Wnt hyperactivation. Stinkingly, we found that transformation into spheroids is associated with a fetal-progenitor signature that drives reprogramming of the circadian clock. A fetal-progenitor signature and circadian reprogramming were also found in human colon tumors. Utilizing RNA-sequencing analysis, we defined a combined circadian clock and fetal risk score that accurately predicts patient survival. Overall, our findings demonstrate a previously unidentified link between a fetal-progenitor state and circadian reprogramming in CRC that is associated with late-stage disease.
Additionally, the role of circadian control of antitumor immunity in colorectal cancer progression is not well understood. To address this, we used a single-cell RNA sequencing approach and found that circadian clock disruption promotes the accumulation of immunosuppressive myeloid cells and subsequent suppression of cytotoxic CD8+ T cells. Epithelial cell clock disruption promotes secretion of inflammatory cytokines and recruits immunosuppressive myeloid cells. Lastly, we demonstrated that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive myeloid cells. Collectively, this suggests that circadian control of tumor immunosuppression affects the efficacy of immune checkpoint blockade.