Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis

Nature Cancer volume 5, pages 546–556 (2024)Cite this article

Subjects

Abstract

The circadian clock regulates daily rhythms of numerous physiological activities through tightly coordinated modulation of gene expression and biochemical functions. Circadian disruption is associated with enhanced tumor formation and metastasis via dysregulation of key biological processes and modulation of cancer stem cells (CSCs) and their specialized microenvironment. Here, we review how the circadian clock influences CSCs and their local tumor niches in the context of different stages of tumor metastasis. Identifying circadian therapeutic targets could facilitate the development of new treatments that leverage circadian modulation to ablate tumor-resident CSCs, inhibit tumor metastasis and enhance response to current therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Core circadian timing systems in mammals.
Fig. 2: Crosstalk between CSCs and the TME promotes metastasis in different cancer types.
Fig. 3: The circadian clock regulates CSCs and their local tumor niches from primary to distant sites.

Similar content being viewed by others

References

  1. Roenneberg, T. & Merrow, M. The circadian clock and human health. Curr. Biol. 26, R432–R443 (2016).

    Article  CAS  PubMed  Google Scholar 

  2. Hastings, M. H., Maywood, E. S. & Brancaccio, M. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat. Rev. Neurosci. 19, 453–469 (2018).

    Article  CAS  PubMed  Google Scholar 

  3. Koronowski, K. B. & Sassone-Corsi, P. Communicating clocks shape circadian homeostasis. Science 371, eabd0951 (2021).

  4. Laothamatas, I., Rasmussen, E. S., Green, C. B. & Takahashi, J. S. Metabolic and chemical architecture of the mammalian circadian clock. Cell Chem. Biol. 30, 1033–1052 (2023).

    Article  CAS  PubMed  Google Scholar 

  5. Straif, K. et al. Carcinogenicity of shift-work, painting, and fire-fighting. Lancet Oncol. 8, 1065–1066 (2007).

    Article  PubMed  Google Scholar 

  6. Oshima, T. et al. Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer. Oncol. Rep. 25, 1439–1446 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Huisman, S. A. et al. Disruption of clock gene expression in human colorectal liver metastases. Tumour Biol. 37, 13973–13981 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Liu, K. et al. Reprogramming the tumor microenvironment by genome editing for precision cancer therapy. Mol. Cancer 21, 98 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Oskarsson, T., Batlle, E. & Massague, J. Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14, 306–321 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Prasetyanti, P. R. & Medema, J. P. Intra-tumor heterogeneity from a cancer stem cell perspective. Mol. Cancer 16, 41 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Korkaya, H. et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol. Cell 47, 570–584 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sharma, V. P., Anderson, N. T. & Geusz, M. E. Circadian properties of cancer stem cells in glioma cell cultures and tumorspheres. Cancer Lett. 345, 65–74 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. Schmitt, K. et al. Circadian control of DRP1 activity regulates mitochondrial dynamics and bioenergetics. Cell Metab. 27, 657–666 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. Patke, A., Young, M. W. & Axelrod, S. Molecular mechanisms and physiological importance of circadian rhythms. Nat. Rev. Mol. Cell Biol. 21, 67–84 (2020).

    Article  CAS  PubMed  Google Scholar 

  15. Takahashi, J. S. Transcriptional architecture of the mammalian circadian clock. Nat. Rev. Genet. 18, 164–179 (2017).

    Article  CAS  PubMed  Google Scholar 

  16. Narasimamurthy, R. & Virshup, D. M. The phosphorylation switch that regulates ticking of the circadian clock. Mol. Cell 81, 1133–1146 (2021).

    Article  CAS  PubMed  Google Scholar 

  17. Wang, Y., Guo, H. & He, F. Circadian disruption: from mouse models to molecular mechanisms and cancer therapeutic targets. Cancer Metastasis Rev. 42, 297–322 (2023).

    Article  CAS  PubMed  Google Scholar 

  18. Dibner, C., Schibler, U. & Albrecht, U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu. Rev. Physiol. 72, 517–549 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Ray, S. et al. Circadian rhythms in the absence of the clock gene Bmal1. Science 367, 800–806 (2020).

    Article  CAS  PubMed  Google Scholar 

  20. Ness-Cohn, E., Allada, R. & Braun, R. Comment on ‘Circadian rhythms in the absence of the clock gene Bmal1’. Science 372, eabe9230 (2021).

  21. Ray, S. et al. Response to comment on ‘Circadian rhythms in the absence of the clock gene Bmal1’. Science 372, eabf1930 (2021).

  22. Kondratov, R. V., Kondratova, A. A., Gorbacheva, V. Y., Vykhovanets, O. V. & Antoch, M. P. Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. Genes Dev. 20, 1868–1873 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kettner, N. M. et al. Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell 30, 909–924 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Puram, R. V. et al. Core circadian clock genes regulate leukemia stem cells in AML. Cell 165, 303–316 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wu, J. et al. Disruption of the clock component Bmal1 in mice promotes cancer metastasis through the PAI-1–TGF-β–myoCAF-dependent mechanism. Adv. Sci. 10, e2301505 (2023).

  26. Hadadi, E. et al. Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice. Nat. Commun. 11, 3193 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Papagiannakopoulos, T. et al. Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab. 24, 324–331 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jiang, W. et al. The circadian clock gene Bmal1 acts as a potential anti-oncogene in pancreatic cancer by activating the p53 tumor suppressor pathway. Cancer Lett. 371, 314–325 (2016).

    Article  CAS  PubMed  Google Scholar 

  29. Miki, T., Matsumoto, T., Zhao, Z. & Lee, C. C. p53 regulates Period2 expression and the circadian clock. Nat. Commun. 4, 2444 (2013).

    Article  PubMed  Google Scholar 

  30. El-Athman, R. et al. The Ink4a/Arf locus operates as a regulator of the circadian clock modulating RAS activity. PLoS Biol. 15, e2002940 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Filipski, E. et al. Effects of light and food schedules on liver and tumor molecular clocks in mice. J. Natl Cancer Inst. 97, 507–517 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Wu, M. et al. Experimental chronic jet lag promotes growth and lung metastasis of Lewis lung carcinoma in C57BL/6 mice. Oncol. Rep. 27, 1417–1428 (2012).

    CAS  PubMed  Google Scholar 

  33. Chen, J. et al. Downregulation of the circadian rhythm regulator HLF promotes multiple-organ distant metastases in non-small cell lung cancer through PPAR/NF-κb signaling. Cancer Lett. 482, 56–71 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Yang, X. et al. Nuclear receptor expression links the circadian clock to metabolism. Cell 126, 801–810 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Tognini, P. et al. Reshaping circadian metabolism in the suprachiasmatic nucleus and prefrontal cortex by nutritional challenge. Proc. Natl Acad. Sci. USA 117, 29904–29913 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sato, S. et al. Atlas of exercise metabolism reveals time-dependent signatures of metabolic homeostasis. Cell Metab. 34, 329–345 (2022).

    Article  CAS  PubMed  Google Scholar 

  37. Beyaz, S. et al. Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis. Cell Stem Cell 28, 1922–1935 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Masri, S. et al. Lung adenocarcinoma distally rewires hepatic circadian homeostasis. Cell 165, 896–909 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Aiello, I. et al. Circadian disruption promotes tumor-immune microenvironment remodeling favoring tumor cell proliferation. Sci. Adv. 6, eaaz4530 (2020).

  40. Sulli, G. et al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature 553, 351–355 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liu, S. et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports 2, 78–91 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Bocci, F. et al. Toward understanding cancer stem cell heterogeneity in the tumor microenvironment. Proc. Natl Acad. Sci. USA 116, 148–157 (2019).

    Article  CAS  PubMed  Google Scholar 

  43. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pein, M. et al. Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs. Nat. Commun. 11, 1494 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dalerba, P. et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl Acad. Sci. USA 104, 10158–10163 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pang, R. et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 6, 603–615 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Leung, C. et al. Lgr5 marks adult progenitor cells contributing to skeletal muscle regeneration and sarcoma formation. Cell Rep. 33, 108535 (2020).

    Article  CAS  PubMed  Google Scholar 

  50. Fatehullah, A. et al. A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers. Nat. Cell Biol. 23, 1299–1313 (2021).

    Article  CAS  PubMed  Google Scholar 

  51. de Sousa e Melo, F. et al. A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature 543, 676–680 (2017).

    Article  PubMed  Google Scholar 

  52. Zhuang, J. et al. Cancer-associated fibroblast-derived miR-146a-5p generates a niche that promotes bladder cancer stemness and chemoresistance. Cancer Res. 83, 1611–1627 (2023).

    Article  CAS  PubMed  Google Scholar 

  53. Nallasamy, P. et al. Pancreatic tumor microenvironment factor promotes cancer stemness via SPP1–CD44 axis. Gastroenterology 161, 1998–2013 (2021).

    Article  CAS  PubMed  Google Scholar 

  54. Yagita, K. et al. Development of the circadian oscillator during differentiation of mouse embryonic stem cells in vitro. Proc. Natl Acad. Sci. USA 107, 3846–3851 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Matsu-Ura, T. et al. Intercellular coupling of the cell cycle and circadian clock in adult stem cell culture. Mol. Cell 64, 900–912 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dierickx, P., Van Laake, L. W. & Geijsen, N. Circadian clocks: from stem cells to tissue homeostasis and regeneration. EMBO Rep. 19, 18–28 (2018).

    Article  CAS  PubMed  Google Scholar 

  57. Dierickx, P. et al. Circadian networks in human embryonic stem cell-derived cardiomyocytes. EMBO Rep. 18, 1199–1212 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Matsunaga, N. et al. Optimized dosing schedule based on circadian dynamics of mouse breast cancer stem cells improves the antitumor effects of aldehyde dehydrogenase inhibitor. Cancer Res. 78, 3698–3708 (2018).

    Article  CAS  PubMed  Google Scholar 

  59. Cao, H. et al. The Shh/Gli signaling cascade regulates myofibroblastic activation of lung-resident mesenchymal stem cells via the modulation of Wnt10a expression during pulmonary fibrogenesis. Lab. Invest. 100, 363–377 (2020).

    Article  CAS  PubMed  Google Scholar 

  60. Hwang-Verslues, W. W. et al. Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy. Proc. Natl Acad. Sci. USA 110, 12331–12336 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Colangelo, T. et al. Loss of circadian gene Timeless induces EMT and tumor progression in colorectal cancer via Zeb1-dependent mechanism. Cell Death Differ. 29, 1552–1568 (2022).

  62. Papadaki, M. A. et al. Circulating tumor cells with stemness and epithelial-to-mesenchymal transition features are chemoresistant and predictive of poor outcome in metastatic breast cancer. Mol. Cancer Ther. 18, 437–447 (2019).

    Article  CAS  PubMed  Google Scholar 

  63. Li, J., Sharkey, C. C., Wun, B., Liesveld, J. L. & King, M. R. Genetic engineering of platelets to neutralize circulating tumor cells. J. Control. Release 228, 38–47 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Harney, A. S. et al. Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 5, 932–943 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Silver, A. C., Arjona, A., Hughes, M. E., Nitabach, M. N. & Fikrig, E. Circadian expression of clock genes in mouse macrophages, dendritic cells, and B cells. Brain Behav. Immun. 26, 407–413 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Paiva, B. et al. Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile. Blood 122, 3591–3598 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Diamantopoulou, Z. et al. The metastatic spread of breast cancer accelerates during sleep. Nature 607, 156–162 (2022).

    Article  CAS  PubMed  Google Scholar 

  68. Matsumura, R. et al. The role of cell-autonomous circadian oscillation of Cry transcription in circadian rhythm generation. Cell Rep. 39, 110703 (2022).

    Article  CAS  PubMed  Google Scholar 

  69. Hartley, P. S. et al. Timed feeding of mice modulates light-entrained circadian rhythms of reticulated platelet abundance and plasma thrombopoietin and affects gene expression in megakaryocytes. Br. J. Haematol. 146, 185–192 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Wortzel, I., Dror, S., Kenific, C. M. & Lyden, D. Exosome-mediated metastasis: communication from a distance. Dev. Cell 49, 347–360 (2019).

    Article  CAS  PubMed  Google Scholar 

  71. Yeung, C. C. et al. Circadian regulation of protein cargo in extracellular vesicles. Sci. Adv. 8, eabc9061 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Khalyfa, A. et al. Exosomes and metabolic function in mice exposed to alternating dark–light cycles mimicking night shift work schedules. Front. Physiol. 8, 882 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Dong, P. et al. BMAL1 induces colorectal cancer metastasis by stimulating exosome secretion. Mol. Biol. Rep. 49, 373–384 (2022).

    Article  CAS  PubMed  Google Scholar 

  74. Ponert, J. M., Gockel, L. M., Henze, S. & Schlesinger, M. Unfractionated and low molecular weight heparin reduce platelet induced epithelial–mesenchymal transition in pancreatic and prostate cancer cells. Molecules 23, 2690 (2018).

  75. Rodriguez-Martinez, A. et al. Exchange of cellular components between platelets and tumor cells: impact on tumor cells behavior. Theranostics 12, 2150–2161 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ye, X. & Weinberg, R. A. Epithelial–mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol. 25, 675–686 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lee, K. W. et al. PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression. Nat. Commun. 13, 2793 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ocana, O. H. et al. Metastatic colonization requires the repression of the epithelial–mesenchymal transition inducer Prrx1. Cancer Cell 22, 709–724 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Du, B. et al. The transcription factor paired-related homeobox 1 (Prrx1) inhibits adipogenesis by activating transforming growth factor-β (TGFβ) signaling. J. Biol. Chem. 288, 3036–3047 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Fu, L., Pelicano, H., Liu, J., Huang, P. & Lee, C. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111, 41–50 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Abbas, T. & Dutta, A. p21 in cancer: intricate networks and multiple activities. Nat. Rev. Cancer 9, 400–414 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gaucher, J., Montellier, E. & Sassone-Corsi, P. Molecular cogs: interplay between circadian clock and cell cycle. Trends Cell Biol. 28, 368–379 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Fagiani, F. et al. Molecular regulations of circadian rhythm and implications for physiology and diseases. Signal Transduct. Target. Ther. 7, 41 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hernández-Camarero, P., López-Ruiz, E., Marchal, J. A. & Perán, M. Cancer: a mirrored room between tumor bulk and tumor microenvironment. J. Exp. Clin. Cancer Res. 40, 217 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Chen, P. et al. Circadian regulator CLOCK recruits immune-suppressive microglia into the GBM tumor microenvironment. Cancer Discov. 10, 371–381 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Xuan, W. et al. Circadian regulator CLOCK drives immunosuppression in glioblastoma. Cancer Immunol. Res. 10, 770–784 (2022).

  87. Chan, A., Ma, S., Pearson, B. J. & Chan, D. Collagen IV differentially regulates planarian stem cell potency and lineage progression. Proc. Natl Acad. Sci. USA 118, e2021251118 (2021).

  88. Shaashua, L. et al. Stromal expression of the core clock gene Period 2 is essential for tumor initiation and metastatic colonization. Front. Cell Dev. Biol. 8, 587697 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Panda, S. The arrival of circadian medicine. Nat. Rev. Endocrinol. 15, 67–69 (2019).

    Article  PubMed  Google Scholar 

  90. Sulli, G., Manoogian, E. N. C., Taub, P. R. & Panda, S. Training the circadian clock, clocking the drugs, and drugging the clock to prevent, manage, and treat chronic diseases. Trends Pharmacol. Sci. 39, 812–827 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhang, J., Lv, H., Ji, M., Wang, Z. & Wu, W. Low circadian clock genes expression in cancers: a meta-analysis of its association with clinicopathological features and prognosis. PLoS ONE 15, e0233508 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cadenas, C. et al. Loss of circadian clock gene expression is associated with tumor progression in breast cancer. Cell Cycle 13, 3282–3291 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Brown, J. R. et al. Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer. JCI Insight 5, e133247 (2020).

  94. Hirota, T. et al. Identification of small molecule activators of cryptochrome. Science 337, 1094–1097 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Miller, S. et al. CRY2 isoform selectivity of a circadian clock modulator with antiglioblastoma efficacy. Proc. Natl Acad. Sci. USA 119, e2203936119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Dong, Z. et al. Targeting glioblastoma stem cells through disruption of the circadian clock. Cancer Discov. 9, 1556–1573 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Xia, L. et al. RORγt agonist enhances anti-PD-1 therapy by promoting monocyte-derived dendritic cells through CXCL10 in cancers. J. Exp. Clin. Cancer Res. 41, 155 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mahalingam, D. et al. Phase 1 open-label, multicenter study of first-in-class RORγ agonist LYC-55716 (cintirorgon): safety, tolerability, and preliminary evidence of antitumor activity. Clin. Cancer Res. 25, 3508–3516 (2019).

    Article  CAS  PubMed  Google Scholar 

  99. Printezi, M. I. et al. Toxicity and efficacy of chronomodulated chemotherapy: a systematic review. Lancet Oncol. 23, e129–e143 (2022).

    Article  CAS  PubMed  Google Scholar 

  100. Lévi, F., Zidani, R. & Misset, J. L. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet 350, 681–686 (1997).

    Article  PubMed  Google Scholar 

  101. von Roemeling, R. & Hrushesky, W. J. Circadian patterning of continuous floxuridine infusion reduces toxicity and allows higher dose intensity in patients with widespread cancer. J. Clin. Oncol. 7, 1710–1719 (1989).

    Article  Google Scholar 

  102. Innominato, P. F., Karaboue, A., Bouchahda, M., Bjarnason, G. A. & Lévi, F. A. The future of precise cancer chronotherapeutics. Lancet Oncol. 23, e242 (2022).

    Article  CAS  PubMed  Google Scholar 

  103. Kroemer, G., Senovilla, L., Galluzzi, L., Andre, F. & Zitvogel, L. Natural and therapy-induced immunosurveillance in breast cancer. Nat. Med. 21, 1128–1138 (2015).

    Article  CAS  PubMed  Google Scholar 

  104. Cervantes-Silva, M. P. et al. The circadian clock influences T cell responses to vaccination by regulating dendritic cell antigen processing. Nat. Commun. 13, 7217 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ince, L. M. et al. Influence of circadian clocks on adaptive immunity and vaccination responses. Nat. Commun. 14, 476 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang, C. et al. Dendritic cells direct circadian anti-tumour immune responses. Nature 614, 136–143 (2023).

    Article  CAS  PubMed  Google Scholar 

  107. Qian, D. C. et al. Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study. Lancet Oncol. 22, 1777–1786 (2021).

    Article  CAS  PubMed  Google Scholar 

  108. Karaboué, A. et al. Time-dependent efficacy of checkpoint inhibitor nivolumab: results from a pilot study in patients with metastatic non-small-cell lung cancer. Cancers 14, 896 (2022).

  109. Kim, E. B. et al. Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature 479, 223–227 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Chun, S. K. et al. Disruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer. Sci. Adv. 8, eabo2389 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Talib, W. H., Alsayed, A. R., Abuawad, A., Daoud, S. & Mahmod, A. I. Melatonin in cancer treatment: current knowledge and future opportunities. Molecules 26, 2506 (2021).

  112. Mu, Q. & Najafi, M. Modulation of the tumor microenvironment (TME) by melatonin. Eur. J. Pharmacol. 907, 174365 (2021).

    Article  CAS  PubMed  Google Scholar 

  113. Van Dycke, K. C. et al. Chronically alternating light cycles increase breast cancer risk in mice. Curr. Biol. 25, 1932–1937 (2015).

    Article  PubMed  Google Scholar 

  114. Li, X. M., Claustrat, B., Hastings, M. H., Albrecht, U. & Lévi, F. [Interactions between clock gene mutation, circadian phenotype and tumor growth in mice]. Pathol. Biol. 55, 194–197 (2007).

    Article  PubMed  Google Scholar 

  115. Huber, A. L. et al. CRY2 and FBXL3 cooperatively degrade c-MYC. Mol. Cell 64, 774–789 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ozturk, N., Lee, J. H., Gaddameedhi, S. & Sancar, A. Loss of cryptochrome reduces cancer risk in p53 mutant mice. Proc. Natl Acad. Sci. USA 106, 2841–2846 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Qu, M. et al. Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle. Proc. Natl Acad. Sci. USA 120, e2214829120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank D. Lane, Y. Zhang, J. Yeong and J. Wang for editing the manuscript. Our work was funded by the Agency for Science, Technology and Research (A*STAR) of Singapore and the Singapore Ministry of Health’s National Medical Research Council under OFIRG23jan-0037. H.G. is also supported by the Program of Shanghai Academic Research Leader (22XD1423400).

Author information

Authors and Affiliations

  1. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    Yu Wang

  2. Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Yu Wang, Yuezhen Xue & Nick Barker

  3. Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Yu Wang, Nuolin Shi & Haidong Guo

  4. Program in Cancer and Stem Cell Biology, Duke–NUS Medical School, Singapore, Singapore

    Rajesh Narasimamurthy

  5. The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China

    Meng Qu

  6. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Nick Barker

Authors
  1. Yu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rajesh Narasimamurthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meng Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nuolin Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haidong Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuezhen Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nick Barker
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.W. wrote the manuscript and made the figures. R.N., M.Q., N.S. and Y.X. conceived the structure of the manuscript and revised the manuscript. N.B., Y.X. and H.G. reviewed and edited the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Haidong Guo, Yuezhen Xue or Nick Barker.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Cancer thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Narasimamurthy, R., Qu, M. et al. Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis. Nat Cancer 5, 546–556 (2024). https://doi.org/10.1038/s43018-024-00759-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s43018-024-00759-4

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer