SNARE-Mediated Regulation of MT1-MMP Trafficking, Invadopodia Formation and Tumour Cell Invasion
Cellular remodeling of the extracellular matrix (ECM), facilitating tumour cell invasion, is a critical step in metastasis and as such is an important area of research to enhance our understanding of cancer biology. To move through the ECM, cells utilize integrins to bind to ECM proteins and proteases to degrade the matrix and in invasive tumour cells, these processes can occur through unique small subcellular structures called invadopodia. Trafficking of key proteins involved in alterations to cell-ECM interactions (including integrins and MMPs) is an important element in tumour cell invasion; however, the mechanisms controlling this trafficking are poorly understood. A protein family that has a major role in vesicle trafficking, SNAREs (soluble N-ethylmaleimide-sensitive factor activating protein receptors), function to localize vesicles to target membranes. The goals of this research were to identify SNARE involvement in membrane-type 1 matrix metalloproteinase (MT1-MMP) trafficking and in invadopodia formation. MT1-MMP was identified as crucial cargo being required for cell invasion in two different breast carcinoma cell lines. Initial studies further determined that SNAREs (SNAP23, Syntaxin13, and VAMP3) are involved in MT1-MMP delivery to the plasma membrane. Also, we have advanced our understanding of how MT1-MMP is recycled to the plasma membrane, and it is now clear that this occurs through a late endosomal route involving VAMP7. Trafficking of MT1-MMP specifically to invadopodia was also investigated and discovered to occur similarly through a VAMP7-mediated route involving SNAP23 and Syntaxin4. Furthermore, we have identified the involvement of SNARE-mediated trafficking in the transport of Src and epidermal growth factor receptor to invadopodia supporting the formation of these structures. These results highlight a role for SNARE- mediated membrane trafficking in cellular invasion.