肿瘤的转移扩散是通过循环肿瘤细胞(ctc)的血液播散实现的。然而，一般来说，决定具有转移能力的ctc产生的时间动态在很大程度上是不明确的，通常认为ctc是不断从生长的肿瘤中脱落或由于机械损伤而脱落的。

在这项新研究中，为了调查循环肿瘤细胞的转移特征，研究人员招募了30名患有进展期乳腺癌的住院女性患者，其中21名患者被诊断为早期乳腺癌（无转移），9名患者在抽血时被诊断为IV期转移性疾病。她们没接受治疗或暂时停止治疗，并在同一天的活动期（上午10:00）和休息期（上午4:00）接受了血液样本采集。

循环肿瘤细胞生成动态的惊人和意想不到的模式：大多数的（78.3%）循环肿瘤细胞出现在休息期（上午4:00）采集的样本中。与患者数据一致，绝大多数（超过90%）循环肿瘤细胞出现在小鼠的休息阶段。与活动期脱落的循环肿瘤细胞相比，休息期脱落的循环肿瘤细胞分裂得更快，因此具有更大的转移倾向。

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.

原文链接：

https://www.nature.com/articles/s41586-022-04875-y

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