AI Article Synopsis

  • The study investigates how MT1-MMP, a protease involved in cancer cell movement, is recruited to invadopodia in metastatic breast cancer cells, focusing on its interaction with a protein called plectin.
  • Through techniques like mass spectrometry and siRNA, researchers found that plectin is crucial for forming invadopodia and facilitating the enzyme's delivery, significantly influencing cancer cell invasiveness.
  • Targeting the MT1-MMP and plectin interaction might pave the way for new therapies aimed at reducing cancer metastasis.

Article Abstract

Background: Invadopodia facilitate cancer cell extravasation, but the molecular mechanism whereby invadopodia-specific proteases such as MT1-MMP are called to invadopodia is unclear.

Methods: Mass spectrometry and immunoprecipitation were used to identify interactors of MT1-MMP in metastatic breast cancer cells. After identification, siRNA and small molecule inhibitors were used to assess the effect these interactors had on cellular invasiveness. The chicken embryo chorioallantoic membrane (CAM) model was used to assess extravasation and invadopodia formation in vivo.

Results: In metastatic breast cancer cells, MT1-MMP was found to associate with plectin, a cytolinker and scaffolding protein. Complex formation between plectin and MT1-MMP launches invadopodia formation, a subtype we termed plectin ( = invadopodial). Plectin delivers MT1-MMP to invadopodia and is indispensable for regulating cell surface levels of the enzyme. Genetic depletion of plectin with siRNA reduced invadopodia formation and cell invasion in vitro. In vivo extravasation efficiency assays and intravital imaging revealed plectin to be a key contributor to invadopodia ultrastructure and essential for extravasation. Pharmacologic inhibition of plectin using the small molecule Plecstatin-1 (PST-1) abrogated MT1-MMP delivery to invadopodia and extravasation efficiency.

Conclusions: Anti-metastasis therapeutic approaches that target invadopodia are possible by disrupting interactions between MT1-MMP and plectin.

Clinical Trial Registration Number: NCT04608357.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369281PMC
http://dx.doi.org/10.1038/s41416-024-02782-9DOI Listing

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