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The metastatic spread of breast cancer accelerates during sleep

Author

Listed:
  • Zoi Diamantopoulou

    (Swiss Federal Institute of Technology (ETH) Zurich)

  • Francesc Castro-Giner

    (Swiss Federal Institute of Technology (ETH) Zurich)

  • Fabienne Dominique Schwab

    (University of Basel
    University Hospital Basel)

  • Christiane Foerster

    (University Hospital Basel
    University Hospital Basel and University of Basel)

  • Massimo Saini

    (Swiss Federal Institute of Technology (ETH) Zurich)

  • Selina Budinjas

    (Swiss Federal Institute of Technology (ETH) Zurich)

  • Karin Strittmatter

    (Swiss Federal Institute of Technology (ETH) Zurich)

  • Ilona Krol

    (Swiss Federal Institute of Technology (ETH) Zurich)

  • Bettina Seifert

    (Cantonal Hospital Basel-Land)

  • Viola Heinzelmann-Schwarz

    (University Hospital Basel)

  • Christian Kurzeder

    (University Hospital Basel
    University Hospital Basel)

  • Christoph Rochlitz

    (University Hospital Basel)

  • Marcus Vetter

    (Cantonal Hospital Basel-Land)

  • Walter Paul Weber

    (University Hospital Basel
    University Hospital Basel and University of Basel)

  • Nicola Aceto

    (Swiss Federal Institute of Technology (ETH) Zurich)

Abstract

The metastatic spread of cancer is achieved by the haematogenous dissemination of circulating tumour cells (CTCs). Generally, however, the temporal dynamics that dictate the generation of metastasis-competent CTCs are largely uncharacterized, and it is often assumed that CTCs are constantly shed from growing tumours or are shed as a consequence of mechanical insults1. Here we observe a striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and mouse models, highlighting that most spontaneous CTC intravasation events occur during sleep. Further, we demonstrate that rest-phase CTCs are highly prone to metastasize, whereas CTCs generated during the active phase are devoid of metastatic ability. Mechanistically, single-cell RNA sequencing analysis of CTCs reveals a marked upregulation of mitotic genes exclusively during the rest phase in both patients and mouse models, enabling metastasis proficiency. Systemically, we find that key circadian rhythm hormones such as melatonin, testosterone and glucocorticoids dictate CTC generation dynamics, and as a consequence, that insulin directly promotes tumour cell proliferation in vivo, yet in a time-dependent manner. Thus, the spontaneous generation of CTCs with a high proclivity to metastasize does not occur continuously, but it is concentrated within the rest phase of the affected individual, providing a new rationale for time-controlled interrogation and treatment of metastasis-prone cancers.

Suggested Citation

  • Zoi Diamantopoulou & Francesc Castro-Giner & Fabienne Dominique Schwab & Christiane Foerster & Massimo Saini & Selina Budinjas & Karin Strittmatter & Ilona Krol & Bettina Seifert & Viola Heinzelmann-S, 2022. "The metastatic spread of breast cancer accelerates during sleep," Nature, Nature, vol. 607(7917), pages 156-162, July.
  • Handle: RePEc:nat:nature:v:607:y:2022:i:7917:d:10.1038_s41586-022-04875-y
    DOI: 10.1038/s41586-022-04875-y
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    Cited by:

    1. Xiaoxu Guo & Fanghe Lin & Chuanyou Yi & Juan Song & Di Sun & Li Lin & Zhixing Zhong & Zhaorun Wu & Xiaoyu Wang & Yingkun Zhang & Jin Li & Huimin Zhang & Feng Liu & Chaoyong Yang & Jia Song, 2022. "Deep transfer learning enables lesion tracing of circulating tumor cells," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Carolin Ector & Christoph Schmal & Jeff Didier & Sébastien De Landtsheer & Anna-Marie Finger & Francesca Müller-Marquardt & Johannes H. Schulte & Thomas Sauter & Ulrich Keilholz & Hanspeter Herzel & A, 2024. "Time-of-day effects of cancer drugs revealed by high-throughput deep phenotyping," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Daniela Michelatti & Sven Beyes & Chiara Bernardis & Maria Luce Negri & Leonardo Morelli & Naiara Garcia Bediaga & Vittoria Poli & Luca Fagnocchi & Sara Lago & Sarah D’Annunzio & Nicole Cona & Ilaria , 2024. "Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory," Nature Communications, Nature, vol. 15(1), pages 1-24, December.

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