MT1-MMP targeting to endolysosomes is mediated by upregulation of flotillins

Area of Science:

• Cell Biology
• Cancer Research
• Molecular Oncology

Background:

• Tumor cell invasion and metastasis are primary causes of cancer mortality.
• Extracellular matrix (ECM) degradation by invadopodia is crucial for metastasis.
• The enzyme MT1-MMP (MMP14) is essential for ECM degradation and is stored in endolysosomes.

Purpose of the Study:

• To elucidate the mechanism of MT1-MMP targeting to endolysosomes.
• To investigate the role of flotillins in MT1-MMP trafficking and cancer invasion.

Main Methods:

• Studied the effect of flotillin upregulation and knockdown on MT1-MMP endocytosis and localization.
• Utilized RAB5 and RAB7 endosomal markers to track MT1-MMP.
• Assessed ECM degradation and cell invasion assays in carcinoma and sarcoma models.

Main Results:

• Flotillin upregulation promotes RAB5-dependent MT1-MMP endocytosis and delivery to RAB7-positive endolysosomes.
• Flotillin knockdown significantly reduces MT1-MMP accumulation in endolysosomes, its exocytosis at invadopodia, and subsequent ECM degradation.
• Flotillin controls MT1-MMP trafficking to the endolysosomal recycling compartment, impacting cancer cell invasion.

Conclusions:

• Flotillin upregulation is necessary and sufficient for promoting cancer cell invasion and ECM degradation.
• Flotillins regulate MT1-MMP endocytosis and endolysosomal trafficking, representing a potential therapeutic target for metastasis.