supervisor: Frédéric Saltel
Involvement of invadosomes in tumor invasion through two examples, Ruvbl2 in molecular organization and DDR2 in angiogenesis
Metastasis is the main cause of death in cancer patients. Around 90% of all deaths are attributed to tumor invasion. Invadosomes are F-actin structures known to be involved in the metastatic process, particularly through their function of extracellular matrix degradation. This promotes the migration of cells into the extracellular matrix, and enables them to cross anatomical barriers such as vessel walls. In this thesis, I focused on the role of Ruvbl2 in invadosome formation and activity. Ruvbl2 is an AAA+ATPase, member of the R2TP complex, which plays a chaperoning role in the formation of big protein complexes and is found enriched in rosette-shaped invadosomes. I have contributed to demonstrating that Ruvbl2 is involved in the process of invadosome formation and, more specifically, in the organization of these structures into rosettes, via the R2TP complex. This complex protects several proteins involved in invadosome formation, including Fak, from autophagic degradation. I was also interested in the regulation of angiogenesis via invadosome formation and activity in endothelial cells. I demonstrated that, in the presence of type I fibrillar collagen, proteasome interacts with DDR2 receptor and negatively regulates invadosome activity. Proteasome inhibition drastically increases invadosome degradation activity. This inhibition stimulates DDR2 activation, mainly by Src. These results underline the importance of a balance between Src and proteasome activity to avoid cell death. Finally, this work provides a better understanding of mechanisms of induction, formation and regulation of invadosomes. It highlights a set of proteins and functions linked to these invasive structures that could be pharmacologically targeted to inhibit metastasis.
Key words : Cancer – Invadosomes – Invasion – Ruvbl2 – R2TP – DDR2