The metastatic spread of cancer is achieved by the haematogenous dissemination of circulating tumour cells (CTCs). Generally, however, the temporal dy

The metastatic spread of breast cancer accelerates during sleep

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2022-06-24 00:00:06

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.

RNA-seq data have been deposited in the Gene Expression Omnibus (GEO, National Center for Biotechnology Information; accession number GSE180097). Processed transcriptomics data, large datasets and other files required for reproducibility are available from the Zenodo data repository (https://doi.org/10.5281/zenodo.6358987). The human reference genome (GRCh38), mouse reference genome (GRCm38), human gene annotation (release 35) and mouse gene annotation (release M25) files were downloaded from GENCODE (https://www.gencodegenes.org). Gene sets were downloaded from the Molecular Signatures Database (MsigDB, v7.4, http://www.gsea-msigdb.org/gsea/msigdb/collections.jsp). All data are available from the corresponding author upon reasonable request. Source data are provided with this paper.