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

Tumor cell invasion and metastasis formation are the major cause of death in cancer patients. They rely on extracellular matrix (ECM) degradation mediated by organelles termed invadopodia, where the transmembrane matrix metalloproteinase MT1-MMP is delivered, coming from RAB7 endolysosomes, its reservoir compartments in cancer cells. How MT1-MMP is targeted to endolysosomes remains to be elucidated. In many invasive cancers flotillin 1 and 2 are upregulated. Here, we show that flotillin upregulation, triggers a general mechanism, common to carcinoma and sarcoma, that promotes RAB5-dependent MT1-MMP endocytosis and its delivery to RAB7-positive endolysosomal reservoirs. Conversely, flotillin knock-down in invasive cancer cells greatly reduces MT1-MMP accumulation in endolysosomes, its subsequent exocytosis at invadopodia, ECM degradation and cell invasion. These data demonstrate that flotillin upregulation is necessary and sufficient to promote epithelial and mesenchymal cancer cell invasion and ECM degradation by controlling MT1-MMP endocytosis and delivery to the endolysosomal recycling compartment.