Cancer Cell Extravasation Requires iPlectin Mediated Choreography of MT1-MMP at Invadopodia

ABSTRACT: Cancer cell extravasation is a key step of the metastatic cascade and an attractive therapeutic opportunity. Early steps in cancer cell extravasation require formation of tentacle-like protrusions called invadopodia that physically breach the endothelial barrier and degrade extracellular matrix (ECM). However, the mechanisms by which invadopodia-specific proteases such as MT1-MMP are called to invadopodia are unclear. In integrin-activated metastatic breast cancer cells, MT1-MMP was found to associate with plectin, a cytoskeletal linker protein, and vimentin, an intermediate filament (IF) protein. Interestingly, complex formation between plectin MT1-MMP immediately launches invadopodia formation, a subtype we termed iplectin (i=invadopodial). iPlectin (complexes of plectin and MT1-MMP) and vimentin cooperate to deliver and anchor this form of MT1-MMP to invadopodia. Genetic depletion of plectin significantly reduced invadopodia formation and significantly reduced cell invasion in vitro. To ascertain the effects of depleted plectin on metastatic behavior, in vivo extravasation efficiency assays and intravital imaging methods were performed. These assays revealed iplectin to be a key component of invadopodia ultrastructure; loss of plectin abrogated cancer cell extravasation rates. Pharmacological inhibition of plectin using the novel small molecule Plecstatin-1 (PST-1) altered vimentin and microtubule networks and altered MT1-MMP delivery to F-actin puncta, presumably due to inhibition of iplectin. In terms of metastasis dynamics, PST-1 treatment reduced invadopodia formation and extravasation rates. Hence, iplectin is responsible for MT1-MMP being called to invadopodia and the most therapeutically relevant form of plectin.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Jennifer Geddes-McAlister  

LAB HEAD: Jennifer Geddes-McAlister

PROVIDER: PXD039276 | Pride | 2025-03-28

REPOSITORIES: Pride