Filopodia and the metastatic cascade
Ponente: Guillaume Jacquemet
Turku Centre for Biotechnology, University of Turku [Turku, Finland]
Host: José María de Pereda
Salón de actos del Centro de Investigación del Cáncer
The formation of metastases is responsible for 90% of deaths in patients with solid tumours. Consequently, there is a pressing need to develop therapeutic strategies that block the ability of cancer cell to disseminate throughout the body. We and others have made an intriguing discovery that cancer metastasis is associated with the development of specialized cellular protrusions called filopodia. In migrating cells, filopodia are “antenna-like” protrusions, which contain cell-surface adhesion receptors, such as integrins, responsible for constantly probing the cellular environment. We discovered that myosin-X contribute to cancer cell metastases in vitro and in vivo models and that myosin-X is highly expressed in patient samples (including breast, pancreatic, colorectal, glioma and lung carcinoma) where it correlates with poor prognosis. Mechanistically, we found that myosin-X-mediated transport of integrins, together with integrin signalling in filopodia are two important prerequisites for cancer metastasis. To understand how filopodia adhesions sense the ECM, we performed a structured-illumination-microscopy (SIM)-based screen to map the localization of 80 target proteins, linked to cell adhesion and migration, within filopodia. Our mapping reveals that filopodia adhesions consist of a unique set of proteins, the filopodome, that are distinct from classical nascent adhesions, focal adhesions, and fibrillar adhesions. In addition, using live imaging, we observe that filopodia adhesions can give rise to nascent adhesions, which, in turn, form focal adhesions. We demonstrate that p130Cas (BCAR1) is recruited to filopodia tips via its C-terminal Cas family homology domain (CCHD) and acts as a mechanosensitive regulator of filopodia stability. We are now using this map to understand how integrin are activated in filopodia tips and how these protein contribute to filopodia formation, directional migration and the different step of the metastatic cascade.