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

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...

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Published inScience advances Vol. 8; no. 32; p. eabo2389
Main Authors Chun, Sung Kook, Fortin, Bridget M, Fellows, Rachel C, Habowski, Amber N, Verlande, Amandine, Song, Wei A, Mahieu, Alisa L, Lefebvre, Austin E Y T, Sterrenberg, Jason N, Velez, Leandro M, Digman, Michelle A, Edwards, Robert A, Pannunzio, Nicholas R, Seldin, Marcus M, Waterman, Marian L, Masri, Selma
Format Journal Article
LanguageEnglish
Published United States American Association for the Advancement of Science 12.08.2022
Subjects
Biomedicine and Life Sciences
Cancer
Circadian Clocks - genetics
Circadian Rhythm - genetics
Colorectal Neoplasms - genetics
Colorectal Neoplasms - metabolism
Humans
Loss of Heterozygosity
Molecular Biology
Organoids - metabolism
SciAdv r-articles
Wnt Signaling Pathway
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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 driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving loss of heterozygosity, which hyperactivates Wnt signaling. This up-regulates , 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.
AbstractList 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. Disruption of the circadian clock accelerates CRC progression by driving Apc loss of heterozygosity.
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.
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 driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving loss of heterozygosity, which hyperactivates Wnt signaling. This up-regulates , 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.
Author Seldin, Marcus M
Verlande, Amandine
Waterman, Marian L
Sterrenberg, Jason N
Edwards, Robert A
Pannunzio, Nicholas R
Velez, Leandro M
Mahieu, Alisa L
Digman, Michelle A
Habowski, Amber N
Masri, Selma
Lefebvre, Austin E Y T
Song, Wei A
Chun, Sung Kook
Fortin, Bridget M
Fellows, Rachel C
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  organization: Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
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  givenname: Rachel C
  orcidid: 0000-0001-6454-7062
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  givenname: Amber N
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  givenname: Amandine
  orcidid: 0000-0001-6794-4119
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  givenname: Wei A
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  orcidid: 0000-0003-1744-2211
  surname: Mahieu
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  organization: Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA
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  surname: Sterrenberg
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  organization: Department of Medicine, University of California, Irvine, Irvine, CA 92697, USA
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  surname: Velez
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  surname: Edwards
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  organization: Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA
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  fullname: Pannunzio, Nicholas R
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  givenname: Marcus M
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  surname: Masri
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  organization: Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
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These authors contributed equally to this work.
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Snippet An alarming rise in young onset colorectal cancer (CRC) has been reported; however, the underlying molecular mechanism remains undefined. Suspected risk...
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StartPage eabo2389
SubjectTerms Biomedicine and Life Sciences
Cancer
Circadian Clocks - genetics
Circadian Rhythm - genetics
Colorectal Neoplasms - genetics
Colorectal Neoplasms - metabolism
Humans
Loss of Heterozygosity
Molecular Biology
Organoids - metabolism
SciAdv r-articles
Wnt Signaling Pathway
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Title Disruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer
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