Ovarian cancer is the most lethal gynaecological malignancy. Mostly because of late stage diagnosis, the 5-year survival rate is <30%. The major cause of death is associated with the presence of therapy-resistant metastasis. Metastases are cell motility-driven and strongly rely on the interaction between cancer cells and the surrounding environment. In particular, protease-dependent extracellular matrix remodelling plays a pivotal role in cancer invasion and metastasis.
The ECM is a complex network of secreted proteins, including collagens, laminins and proteoglycans, that, besides providing support for tissues and organs, also controls cell migration, proliferation and oncogenic transformation. The tumour microenvironment, including the ECM, has a pivotal role in modulating cancer initiation, progression and metastasis, while cancer cells in turn modify the composition and properties of the ECM, demonstrating a bi-directional interaction between tumour and stroma. It has become apparent that the ECM composition and properties change dramatically during cancer progression, leading to the formation of a tumour-promoting environment.
Versican (VCAN) is a proteoglycan of the lectican family, involved in controlling several cell functions, including adhesion, proliferation, migration and ECM assembly. In particular, ovarian cancer cells have been shown to stimulate the expression and secretion of VCAN by cancer-associated fibroblasts, which is required for cancer cell migration and invasion. VCAN is cleaved by a family of zinc-dependent metalloproteases, A Disintegrin And Metalloproteinase Domain with TromboSpondin type I module (ADAMTS), composed of 19 members of secreted proteases, including ADAMTS5. Vesicular trafficking is essential for the polarised distribution of transmembrane receptors and secreted molecules. It is controlled by Rabs, small GTPases of the Ras family, which control vesicle identity and cargo delivery. Therefore, it is not surprising that alterations in Rab expression and function have been associated with cancer. In particular, epithelial specific Rab25, a member of the Rab11 family, has been shown to promote ovarian cancer cell migration and invasion. Consistent with this, high Rab25 expression correlates with poor prognosis in ovarian cancer. Our preliminary data indicate that Rab25 induces the expression of ADAMTS5, and this is required to support ovarian cancer cell invasive migration.
Using advanced fixed and live cell imaging techniques and 3D cell culture systems, this project will:
- Characterise the molecular mechanisms through which Rab25 controls ADAMTS5 expression
- Elucidate the mechanisms through which ADAMTS5 modulate ovarian cancer cell migration
- Define whether ADAMTS5 is required for ovarian cancer progression and invasion
Despite the incidence and mortality of ovarian cancer, the mechanisms controlling metastasis are not fully understood. The outcome of this project will deepen our understanding of the interplay between cancer cells and the ECM, highlighting whether ADAMTS5 can represent a novel target for the development of new ovarian cancer therapies.
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