The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research. Previously known as our Top 10 Cancer Research Publications, it is curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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Diamantopoulou, Z., Castro-Giner, F., Schwab, F.D. et al. Nature 607, 156–162 (2022).
doi: 10.1038/s41586-022-04875-y.
Summary of findings
Distant metastasis is achieved by the hematogenous dissemination of circulating tumor cells (CTCs). However, the temporal dynamics that dictate the generation of metastasis-competent CTCs have been often neglected, assuming that CTCs are constantly shed from growing tumors or shed as a consequence of mechanical insults. We observe a striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and mouse models, highlighting that the vast majority of spontaneous CTC intravasation events occur during sleep. We demonstrate that rest-phase CTCs are highly metastasis-prone compared to CTCs that are generated during the active phase. Mechanistically, single cell-resolution RNA sequencing analysis of CTCs reveals a dramatic upregulation of mitotic genes during the rest phase in both patients and mouse models, enabling metastasis proficiency. At the systemic level, 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 tumor cell proliferation in vivo, yet in a time-dependent manner. Thus, the spontaneous generation of CTCs with a high metastatic ability does not occur continuously, but it is concentrated within the rest phase of the host, providing a new rationale for time-controlled interrogation and treatment of metastasis-prone cancers.
