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Cancer cell extravasation requires iplectin-mediated delivery of MT1-MMP at invadopodia.
Grafinger, Olivia R; Hayward, John J; Meng, Ying; Geddes-McAlister, Jennifer; Li, Yan; Mar, Sara; Sheng, Minzhi; Su, Boyang; Thillainadesan, Gobi; Lipsman, Nir; Coppolino, Marc G; Trant, John F; Jerzak, Katarzyna J; Leong, Hon S.
Afiliación
  • Grafinger OR; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
  • Hayward JJ; Department of Chemistry, University of Windsor, Windsor, ON, Canada.
  • Meng Y; Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
  • Geddes-McAlister J; Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
  • Li Y; Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
  • Mar S; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
  • Sheng M; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
  • Su B; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
  • Thillainadesan G; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
  • Lipsman N; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
  • Coppolino MG; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
  • Trant JF; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
  • Jerzak KJ; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
  • Leong HS; Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Br J Cancer ; 131(5): 931-943, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38969866
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 iplectin (i = invadopodial). iPlectin 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 iplectin 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 iplectin. CLINICAL TRIAL REGISTRATION NUMBER NCT04608357.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Metaloproteinasa 14 de la Matriz / Podosomas / Invasividad Neoplásica Límite: Animals / Female / Humans Idioma: En Revista: Br J Cancer Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Metaloproteinasa 14 de la Matriz / Podosomas / Invasividad Neoplásica Límite: Animals / Female / Humans Idioma: En Revista: Br J Cancer Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido