Loss of primary cilia promotes EphA2-mediated endothelial-to-mesenchymal transition in the ovarian tumor microenvironment

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Endothelial-to-mesenchymal transition (EndMT) is closely associated with tumor progression. Endothelial cells (ECs) in the tumor microenvironment (TME) use EndMT programs to facilitate tumor progression; however, the underlying mechanisms in ovarian cancer are poorly understood. Here, we describe the involvement of primary cilia in EndMT of the ovarian TME. We showed that ECs from human ovarian tumors displayed robust EndMT and impaired cilia formation, as was also observed in ECs in response to ovarian cancer cell culture-conditioned media (OV-CM). Notably, ECs lacking primary cilia exhibited increased OV-CM-induced EndMT. Vascular abnormalities, such as enhanced cell migration and vessel permeability, were observed in vitro. Furthermore, in vivo experiments using endothelial-specific kinesin family member 3A (Kif3a)-knockout mice showed enhanced EndMT in the ovarian TME. Mechanistically, we identified ephrin type-A receptor 2 (EphA2) as a key regulator of EndMT. Upon OV-CM treatment, EphA2 expression increased, and depletion of EphA2 in ECs decreased OV-CM-induced EndMT and vascular abnormalities. These results highlight that the loss of primary cilia and the consequent EphA2 activation are key mechanisms by which EndMT programs induce the acquisition of cancer-associated fibroblast-like cells in the ovarian TME, thereby promoting ovarian cancer progression.

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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