The metastatic spread of breast cancer accelerates during sleep

Abstract

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 1 . Here, 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 the rest phase. Further, we demonstrate 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 reveals a dramatic 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 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.3/24 Main Circulating tumor cells (CTCs) are pioneers of the metastatic cascade in several cancer types, including breast cancer 1 . The factors that regulate spontaneous CTC intravasation in physiological settings are poorly understood, and the general assumption is that CTCs are constantly generated from invasive cancerous tissues 2 , or generated upon mechanical cues such as surgery 3 or physical activity 4 . In patients and in mouse cancer models, the exact timing of the events that characterize metastatic cancer progression, as well as the principles that dictate CTC intravasation and their proclivity to metastasize are unclear. A better understanding of these processes may result in new approaches for cancer investigation and treatment. Circadian rhythm and CTC intravasationWe first sought to determine CTC abundance and composition in hospitalized women with progressive breast cancer that had no treatment or were temporarily off-treatment and that consented to donate blood during the active (10:00am) and rest (4:00am) phase of the same day, including a total of 30 patients (Fig. 1a). Of these, 21 patients were diagnosed with early breast cancer (no metastasis) and 9 were diagnosed with stage IV metastatic disease at the time of blood sampling (Supplementary Table 1). Strikingly, upon antigen-agnostic microfluidic capture of CTCs and confirmation via immunofluorescence staining 5 , we found the vast majority of CTCs (78.3%) in samples obtained at nighttime during rest phase, including single CTCs, CTC clusters and CTC-white blood cell (WBC) cl...

Novel genomic loci influence patterns of structural covariance in the human brain

“…One previous study showed that common genes might mediate breast cancer metastasis to the brain, 21 and a later study further corroborated that the metastatic spread of breast cancer to other organs (including the brain) accelerated during sleep in both mouse and human models. 38 We further showcased that this brain metastasis of breast cancer might be associated with specific neuropathologic processes, which were captured by PSCs data driven by Alzheimer's diseaserelated neuropathology. For example, the hippocampus-entorhinal cortex PSC (C128_3, Fig.…”

An exploratory study on the checkout rate of circulating tumor cells and the prediction of efficacy of neoadjuvant therapy and prognosis in patients with HER-2-positive early breast cancer

“…Although current clinical practice guidelines do not yet recommend making treatment decisions based on CTCs enumeration or phenotyping for patient with metastatic breast cancer (MBC), multiple studies have confirmed that CTCs are widespread in MBC and high baseline CTC counts based on CellSearch is a well-established independent prognostic factor for worsening progression-free survival (PFS) and overall survival (OS). Moreover, dynamic changes of CTCs have a role in predicting treatment efficacy (4)(5)(6)(7)(8). The checkout rate of CTC in patients with early breast cancer (EBC) is significantly lower than that of MBC, ranging from 21.5% to 24% as reported in previous study, and≥ 1 CTC/7.5ml blood is a poor prognostic factor for disease free survival (DFS) and OS (9)(10)(11)(12).…”

Nocturnal circulating tumor cells: The ultimate selective filter in cancer progression?

“…Using evolutionary ecology reasoning, Corte ´s-Herna ´ndez et al predicted that malignant cells, including CTCs, should behave differently between day and night. 3 Following the recent work of Diamantopoulou et al, 4 this is now a proven fact for CTCs, and this discovery will undoubtedly have major medical implications. Would this suggest that we have so far missed a major adaptive feature of the metastatic process?…”

“…The main findings by Diamantopoulou et al 4 include the following: (1) a correlation between the circadian rhythm and CTC intravasation. Diamantopoulou and colleagues identified a striking and unexpected pattern of CTC-generation dynamics in both patients with breast cancer (n = 30; 21 patients were diagnosed with early breast cancer-no metastasis-and 9 were diagnosed with stage IV metastatic disease) as well as in four different mouse models.…”