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Disruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer.

ABSTRACT: An alarming rise in young onset colorectal cancer (CRC) has been reported; however, the underlying molecular mechanism remains undefined. Suspected risk factors of young onset CRC include environmental aspects, such as lifestyle and dietary factors, which are known to affect the circadian clock. 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, which hyperactivates Wnt signaling. This up-regulates c-Myc, a known Wnt target, which drives heightened glycolytic metabolism. Using patient-derived organoids, we show that circadian rhythms are lost in human tumors. Last, we identify that variance between core clock and Wnt pathway genes significantly predicts the survival of patients with CRC. Overall, our findings demonstrate a previously unidentified mechanistic link between clock disruption and CRC, which has important implications for young onset cancer prevention.

SUBMITTER: Chun SK

PROVIDER: S-EPMC9365282 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Disruption of the circadian clock drives <i>Apc</i> loss of heterozygosity to accelerate colorectal cancer.

Chun Sung Kook SK Fortin Bridget M BM Fellows Rachel C RC Habowski Amber N AN Verlande Amandine A Song Wei A WA Mahieu Alisa L AL Lefebvre Austin E Y T AEYT Sterrenberg Jason N JN Velez Leandro M LM Digman Michelle A MA Edwards Robert A RA Pannunzio Nicholas R NR Seldin Marcus M MM Waterman Marian L ML Masri Selma S

Science advances 20220810 32

An alarming rise in young onset colorectal cancer (CRC) has been reported; however, the underlying molecular mechanism remains undefined. Suspected risk factors of young onset CRC include environmental aspects, such as lifestyle and dietary factors, which are known to affect the circadian clock. We find that both genetic disruption and environmental disruption of the circadian clock accelerate <i>Apc-</i>driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clo ...[more]

PMID: 35947664

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Project description:Background & aimsThe circadian clock is crucial for physiological homeostasis including gut homeostasis. Disorder of the circadian clock may contribute to many diseases including inflammatory bowel disease (IBD). However, the role and the mechanisms of circadian clock involvement in IBD still are unclear.MethodsDisorder of the circadian clock including chronic social jet lag and circadian clock gene deficiency mice (Bmal1-/-, and Per1-/-Per2-/-) were established. Dextran sulfate sodium (DSS) and/or azoxymethane were used to induce mouse models of colitis and its associated colorectal cancer. Flow cytometry, immunohistochemistry, immunofluorescence, Western blot, and reverse-transcription quantitative polymerase chain reaction were used to analyze the characteristics of immune cells and their related molecules.ResultsMice with disorders of the circadian clock including chronic social jet lag and circadian clock gene deficiency were susceptible to colitis. Functionally, regulatory B (Breg) cells highly expressing Programmed cell death 1 ligand 1 (PDL1) in intestinal intraepithelial lymphocytes (IELs) helped to alleviate the severity of colitis after DSS treatment and was dysregulated in DSS-treated Bmal1-/- mice. Notably, interleukin 33 in the intestinal microenvironment was key for Bmal1-regulated PDL1+ Breg cells and interleukin 33 was a target of Bmal1 transcriptionally. Dysregulated PDL1+ B cells induced cell death of activated CD4+ T cells in DSS-treated Bmal1-/- mice. Consequently, circadian clock disorder was characterized as decreased numbers of Breg+ PDL1+ cells in IELs and dysfunction of CD4+ T cells promoted colitis-associated colorectal cancer (CRC) in mice. In clinical samples from CRC patients, low expression of Bmal1 gene in paracancerous tissues and center area of tumor was associated closely with a poorer prognosis of CRC patients.ConclusionsOur study uncovers the importance of the circadian clock regulating PDL1+ Breg+ cells of IELs in IBD and IBD-associated CRC.

Dataset Information

Disruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer.

Publications

Disruption of the circadian clock drives <i>Apc</i> loss of heterozygosity to accelerate colorectal cancer.

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