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955 Disruption of the circadian clock accelerates colorectal cancer and promotes immunosuppression
  1. Selma Masri and
  2. Bridget Fortin
  1. University of California, Irvine, Irvine, CA, USA


Background Colorectal cancer (CRC) is the third leading cause of cancer-related deaths and the third most diagnosed cancer in the United States. The circadian clock is the primary biological pacemaker of the body, which controls several physiological, endocrine and metabolic processes that operate to maintain organismal homeostasis. Disruption of this endogenous rhythm and function has been linked to several cancers, yet the precise molecular mechanisms and detailed signaling pathways by which disruption of circadian rhythm is linked to cancer progression have not yet been elucidated. In colorectal cancer specifically, epidemiological evidence links night-shift work with elevated incidence of colorectal cancer (CRC), suggesting that light-at-night exposure could potentially have adverse effects on human physiology. In fact, CRC clinical data reports the downregulation of key clock genes, in addition to metabolic dysregulation.

Methods To address this gap in knowledge, we developed a new genetically engineered mouse model that allows us to look at clinically relevant mutations of colorectal cancer with and without genetic disruption of the clock. From these mice we make organoids that allow us to study the complete intestinal epithelium in an ex vivo setting.

Results Circadian clock disruption was found to accelerate colorectal cancer progression in a novel genetically-engineered mouse model. Both genetic and environmental disruption of the circadian clock promotes the abundance of myeloid cells and suppressed the proportion of cytotoxic T cells in the intestine. Importantly, circadian clock disruption also promotes an inflammatory response in both ex vivo intestinal organoids derived from humans and mice.

Conclusions The circadian clock regulates immunity through suppressing inflammation. It is expected that circadian clock disruption leads to an inflammatory response that, if it persists, can alter the immune landscape in an immunosuppressive manner.

Acknowledgements Bridget Fortin is supported by the T32 Interdisciplinary Cancer Research (IDCR) Training Program. The Masri Lab is supported by the NIH/NCI, The V Foundation, The Concern Foundation, the UC Irvine Chao Family Comprehensive Cancer Center (Anti-Cancer Challenge Seed Grant), the Cancer Research Coordinating Committee and the UC Irvine School of Medicine.

A special thanks to the Experimental Tissue Resource (ETR) and the Institute for Immunology (IFI) Flow Cytometry Core for their advice and expertise.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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