The protease ADAMTS5 controls ovarian cancer cell invasion, downstream of Rab25

Abstract

Ovarian cancer is the 3rd most common gynaecological malignancy worldwide, with a 5-year survival rate of < 30% in the presence of metastasis. Metastatic progression is characterised by extensive remodelling of the extracellular matrix, primarily mediated by secreted proteases, including members of the ‘a disintegrin and metalloprotease with thrombospondin motif’ (ADAMTS) family. In particular, ADAMTS5 has been reported to be upregulated in ovarian malignant tumours compared to borderline and benign lesions, suggesting it might play a role in metastatic progression. Furthermore, it has been suggested that Rab25, a small GTPase of the Ras family, might upregulate ADAMTS5 expression in ovarian cancer cells. Here we demonstrated that Rab25 promotes ADAMTS5 expression through the activation of the nuclear factor κB (NF-κB) signalling pathway. Furthermore, ADAMTS5 was necessary and sufficient to stimulate ovarian cancer cell migration through complex fibroblast-secreted matrices, while selective ADAMTS5 inhibition prevented ovarian cancer spheroid invasion in 3D systems. Finally, in ovarian cancer patients, high ADAMTS5 expression correlated with poor prognosis. Altogether, these data identify ADAMTS5 as a novel regulator of ovarian cancer cell migration and invasion, suggesting it might represent a previously undescribed therapeutic target to prevent ovarian cancer metastasis.