Arrest Of Circulating Tumor Cells Research Articles

Notch-1 signaling promotes reattachment of suspended cancer cells by cdc42-dependent microtentacles formation.

Circulating tumor cells (CTCs) are associated with a higher risk of metastasis in tumor patients. The adhesion and arrest of CTCs at a secondary site is an essential prerequisite for the occurrence of tumor metastasis. CTC reattachment has shown to be dependent on microtentacle (McTN) formation in vivo. However, the specific molecular mechanism of McTN formation in suspended cancer cells remains largely unclear. Here, we demonstrated that the activation of Notch‐1 signaling triggers McTN formation to facilitate cell reattachment in suspended cell culture conditions. Moreover, molecular mechanistic studies revealed that McTN formation is governed by the balance between microtubule‐driven outgrowth and actomyosin‐driven cell contractility. The activation of Notch‐1 downregulates the acetylation level of microtubules via the Cdc42/HDAC6 pathway, which contributes to microtubule polymerization. Simultaneously, Notch‐1 signaling‐induced Cdc42 activation also reduced phosphorylation of myosin regulatory light chain, leading to cell contractility attenuation. Altogether, these results defined a novel mechanism by which Notch‐1 signaling disturbs the balance between the expansion of microtubules and contraction of the cortical actin, which promotes McTN formation and cell reattachment. Our findings provide a new perspective on the effective therapeutic target to prevent CTC reattachment.

RhoA-stimulated intra-capillary morphology switch facilitates the arrest of individual circulating tumor cells.

Metastasis is the primary cause of death for most cancer patients. Hematogenous arrest of circulating tumor cells (CTCs) is an essential prerequisite for metastases formation. Using transparent transgenic zebrafish (kdrl:eGFP; Casper), together with resonant laser scanning confocal microscopy, we tracked the fate of CTCs in vivo in the blood circulation for days. We found the intra-capillary morphology-switch (ICMS) of individual CTCs from strip to sphere was necessary for their intravascular arrests. Further genetic and pharmacological inhibition experiments indicated that the RhoA signaling was necessary for ICMS and the arrest of CTCs. At last, we demonstrated that early treatment by a clinically approved RhoA/ROCK inhibitor, Fasudil, could efficiently inhibit the initial arrest of individual CTCs and reduce the incidence of tumor metastasis in both zebrafish and mouse models. These results together indicate that RhoA-stimulated ICMS represents a mechanism for the arrest of individual CTCs, providing a potential target for future treatments of hematogenous metastatic disease.