RAB14-dependent tubulovesicular recycling directs MET to invadopodia promoting TNBC cell invasion

Abstract

Metastasis is one of the primary causes of cancer-related death in Triple-negative breast cancer patients. During metastatic dissemination, the cancer cells infiltrate in to surrounding tissue employing specialized membrane-protrusion with proteolytic activity called invadopodia. Cues from growth factors via the cognate receptor tyrosine kinases promote invadopodia formation and cancer cell invasion. We report the role of HGF and its cognate receptor MET in TNBC invasion. The results from our study demonstrate that the TNBC cells when stimulated with HGF promotes invadopodia formation and facilitates delivery of MT1-MMP to the invadopodia in a MET dependent manner. We also showed that MET resides at invadopodia and its localization at invadopodia increases upon HGF treatment due to enhanced surface delivery of the RTK. By employing a degradation defective mutant, we demonstrated the critical role of MET recycling in driving breast cancer invasion. Moreover, we observed that the RCP-RAB14 axis mediates the surface delivery of MET through tubulovesicular carriers, with KIF16B promoting the formation of vesicular tubules on RAB14-positive endosomes. Collectively, the study provides mechanistic insights on the growth factor-mediated recycling of RTK and the associated metalloprotease in invadopodia-dependent matrix degradation and cancer cell invasion.