ADAMTS5 and integrin crosstalk in controlling ovarian cancer migration and invasion

Ovarian cancer is the most common cause of female gynaecological cancer death and ~80% of patients will have developed metastasis at diagnosis. For this reason, it is fundamental to discover novel mechanisms controlling ovarian cancer metastasis. Ovarian cancer metastasis relies on cancer cell migration and interaction with the extracellular matrix (ECM), mediated by surface receptors like integrins. Extracellular proteases, like ADAMTSs, are fundamental to degrade the ECM and facilitate cell migration, leading to the formation of a tumour-promoting environment. The small GTPase Rab25 has been shown to control cancer cell migration in 3D environments, increasing integrin recycling. We have recently demonstrated that ADAMTS5 was upregulated by Rab25. Moreover, ADAMTS5 inhibition reduced the migration and invasion of ovarian cancer cells over-expressing Rab25.

In this thesis we showed that the ECM component fibronectin promoted ADAMTS5 expression. Mechanistically, we found that the fibronectin co-receptor syndecan-4 was required for Rab25-driven ADAMTS5 expression. We also found that ADAMTS5 was necessary and sufficient to stimulate ovarian cancer cell migration through matrix, while ADAMTS5 inhibition and knockdown prevented ovarian cancer spheroid invasion and migration through mesothelial cell layers. Furthermore, we developed an in vivo Zebrafish
model to elucidate the contribution of Rab25 to ovarian cancer metastasis and found that Rab25 overexpression promoted ovarian cancer metastasis formation. Altogether, these data identify ADAMTS5 as a novel regulator of ovarian cancer cell migration and invasion, suggesting it might represent a novel therapeutic target to prevent ovarian cancer metastasis.