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...
SummaryAberrant WNT signaling drives colorectal cancer (CRC). Here, we identify TIAM1 as a critical antagonist of CRC progression through inhibiting TAZ and YAP, effectors of WNT signaling. We demonstrate that TIAM1 shuttles between the cytoplasm and nucleus antagonizing TAZ/YAP by distinct mechanisms in the two compartments. In the cytoplasm, TIAM1 localizes to the destruction complex and promotes TAZ degradation by enhancing its interaction with βTrCP. Nuclear TIAM1 suppresses TAZ/YAP interaction with TEADs, inhibiting expression of TAZ/YAP target genes implicated in epithelial-mesenchymal transition, cell migration, and invasion, and consequently suppresses CRC cell migration and invasion. Importantly, high nuclear TIAM1 in clinical specimens associates with increased CRC patient survival. Together, our findings suggest that in CRC TIAM1 suppresses tumor progression by regulating YAP/TAZ activity.
Centrosome separation is critical for bipolar spindle formation and the accurate segregation of chromosomes during mammalian cell mitosis. Kinesin-5 (Eg5) is a microtubule motor essential for centrosome separation, and Tiam1 and its substrate Rac antagonize Eg5-dependent centrosome separation in early mitosis promoting efficient chromosome congression. Here we identify S1466 of Tiam1 as a novel Cdk1 site whose phosphorylation is required for the mitotic function of Tiam1. We find that this phosphorylation of Tiam1 is required for the activation of group I p21-activated kinases (Paks) on centrosomes in prophase. Further, we show that both Pak1 and Pak2 counteract centrosome separation in a kinase-dependent manner and demonstrate that they act downstream of Tiam1. We also show that depletion of Pak1/2 allows cells to escape monopolar arrest by Eg5 inhibition, highlighting the potential importance of this signalling pathway for the development of Eg5 inhibitors as cancer therapeutics.
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