Vasculogenic mimicry (VM) is the formation of vascular endothelial cell-independent microvascular structures by cancer cells. VM is known to be a cause of malignant phenotypes in cancer, but the detailed mechanism is not well understood [1, 2]. In this study, we investigated the role of actin cytoskeleton on VM formation. First, we showed that the treatment with actin dynamics inhibitors, cytochalasin D and jasplakinolide, disrupted the structure of the actin cytoskeleton and VM formation dose dependent manner in MDA-MB-231 human breast cancer cells. According to the results, we established cofilin-knockout (KO) MDA-MB-231 cells using the CRISPR/Cas9 system, because cofilin is a key regulator of actin depolymerization and thereby accelerate actin dynamics. We found that VM formation was attenuated in cofilin-KO cells. Interestingly, structural changes in the cytoskeleton, especially the F-actin content, were observed in cofilin-KO cells. Activity of cofilin is dependent on the phosphorylation at Ser3 residue. Although re-expression of wild-type cofilin restored VM formation in cofilin-KO cells, cofilin/S3E, an inactive phospho-cofilin mimetic, failed to rescue VM formation. Collectively, our results demonstrated that actin dynamics regulate VM formation, and actin-modulating inhibitors may be potent inhibitors for VM formation.
Ref.
1. Simizu S.: Biochim. Biophys. Acta (Gen. Subj.), 1866, 130084 (2022)
2. Kawahara R & Simizu S.: Cancer Sci. 113, 950-9 (2022)