We have found that the circadian rhythm strongly affects the dynamics of CTC generation. (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 govern the generation of metastasis-competent CTCs are largely uncharacterized, with the assumption that CTCs are constantly shed from growing tumors or 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. Furthermore, we demonstrated that rest-phase CTCs are highly prone to metastasis, whereas CTCs generated during the active phase lack metastatic potential. Mechanistically, single-cell-resolution RNA sequencing of CTCs revealed a dramatic upregulation of mitotic genes exclusively during the rest phase in both patients and mouse models, thereby enabling metastasis proficiency. Mechanistically, we found that key circadian rhythm hormones such as melatonin, testosterone, and glucocorticoids govern CTC generation dynamics and, as a consequence, that insulin directly promotes tumor cell proliferation in vivo, albeit in a time-dependent manner. Thus, the spontaneous generation of CTCs with a high proclivity to metastasize does not occur continuously but is concentrated during 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 intravasation process have been completed. These include the characterization of the intracellular heterogeneity of CTC clusters (Gremmelspacher et al., Nature Genetics, 2025), clinical proof-of-concept for CTC cluster disruption (Kurzeder et al., Nature Medicine, 2025), CRISPR screens in immunocompetent models to reveal additional CTC cluster vulnerabilities (Saini et al., Cell, 2025), and the role of Ki67 in breast cancer intravasation (Zhang et al., Cell Reports, 2026).
Exploitation and dissemination of the results have focused on presentations at international conferences or symposia, and ongoing discussions with investors and third parties interested in developing new targeting concepts.
