Tuesday September 25, 2012 10:30 - 11:00 @ Rhodes 6

Tuesday September 25, 2012 12:30 - 14:00 @ Rhodes 6 

RAB5-induced invadosomes formation promotes tumor dissemination

Abstract:

Cancer invasion is frequently initiated and sustained by cytoskeletal dynamics that propels migratory protrusions, and pericellular proteolytic activity that remodels the extracellular matrix (ECM). How these two processes are integrated to decode both soluble biochemical and mechanical microenvironmental cues is still unresolved. Here, we report that RAB5, a small GTPase master regulator of endocytosis, is necessary and sufficient for the formation of invadosomes, specialized membrane protrusions for ECM degradation. RAB5 promotes RAB4-dependent endo/exocytic cycles (EEC) of critical cargos (MT1-MMP and β3 integrin) required for invadosome formation in response to motogenic stimuli. This trafficking circuitry is necessary to spatially resolve HGF/MET signalling into polarized functions required for directional motility, degradation and remodelling of the ECM and, thus, for tumor invasion into interstitial tissues and dissemination to distant organs. Consistently, RAB5 elevated expression tightly correlates with metastatic dissemination of different human tumors. Thus, RAB5 promotes tumor metastasis by coordinating invadosome-mediated matrix degradation with actin-based mesenchymal protrusions.