期刊
JOURNAL OF CELL SCIENCE
卷 131, 期 17, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.218925
关键词
Cancer cell invasion; Extracellular matrix degradation; Endolysosomal vesicular trafficking; Flotillin; MT1-MMP
类别
资金
- Institut National du Cancer [INCa_9483]
- Russian Science Foundation [14-15-00318, 14.594.21.0001]
- Agence Nationale de la Recherche [ANR-10-INBS-04]
- Institut National de la Sante et de la Recherche Medicale
- Fondation pour la Recherche Medicale
- Russian Science Foundation [17-15-00033] Funding Source: Russian Science Foundation
Tumor cell invasion and metastasis formation are the major cause of death in cancer patients. These processes rely on extracellular matrix (ECM) degradation mediated by organelles termed invadopodia, to which the transmembrane matrix metalloproteinase MT1-MMP (also known as MMP14) is delivered from its reservoir, the RAB7-containing endolysosomes. How MT1-MMP is targeted to endolysosomes remains to be elucidated. Flotillin-1 and -2 are upregulated in many invasive cancers. Here, we show that flotillin upregulation triggers a general mechanism, common to carcinoma and sarcoma, which promotes RAB5-dependent MT1-MMP endocytosis and its delivery to RAB7-positive endolysosomal reservoirs. Conversely, flotillin knockdown in invasive cancer cells greatly reduces MT1-MMP accumulation in endolysosomes, its subsequent exocytosis at invadopodia, ECM degradation and cell invasion. Our results 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.
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