We have found that the circadian rhythm strongly affects CTC generation dynamics. (Diamantopoulou et al., Nature, 2022)
Summary:
The metastatic spread of cancer is achieved by the hematogenous dissemination of circulating tumor cells (CTCs). Generally, however, the temporal dynamics that dictate the generation of metastasis-competent CTCs are largely uncharacterized, often assuming that CTCs are constantly shed from growing tumors or shed as a consequence of mechanical insults. In this study, we have observed 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 the rest phase. Further, we demonstrated that rest-phase CTCs are highly metastasis-prone, while CTCs generated during active phase are devoid of metastatic ability. Mechanistically, single cell-resolution RNA sequencing analysis of CTCs revealed a dramatic upregulation of mitotic genes exclusively during the rest phase in both patients and mouse models, enabling metastasis proficiency. Mechanistically, we found 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 proclivity to metastasize 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.
Additional investigations related to the tumor microenvironment, transcriptomic, genomic and epigenomic patterns, as well as the immune system are ongoing.
