The metastatic spread of breast cancer accelerates during sleep

Zoi Diamantopoulou, Francesc Castro-Giner, Fabienne Dominique Schwab, Christiane Foerster, Massimo Saini, Selina Budinjas, Karin Strittmatter, Ilona Krol, Bettina Seifert, Viola Heinzelmann-Schwarz, Christian Kurzeder, Christoph Rochlitz, Marcus Vetter, Walter Paul Weber and Nicola Aceto ()
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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
Christiane Foerster: University Hospital 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
Christoph Rochlitz: University Hospital Basel
Marcus Vetter: Cantonal Hospital Basel-Land
Walter Paul Weber: University Hospital Basel
Nicola Aceto: Swiss Federal Institute of Technology (ETH) Zurich

Nature, 2022, vol. 607, issue 7917, 156-162

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04875-y

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