Abstract
Metastatic melanoma remains the deadliest of all skin cancers with a survival rate at five years of less than 15%. MT1-MMP is a membrane-associated matrix metalloproteinase that controls pericellular proteolysis and is an important, invasion-promoting, pro-tumorigenic MMP in cancer. We show that deregulation of MT1-MMP expression happens as early as the transition from nevus to primary melanoma and continues to increase during melanoma progression. Furthermore, MT1-MMP expression is associated with poor melanoma patient outcome, underscoring a pivotal role of MT1-MMP in melanoma pathogenesis. We demonstrate that MT1-MMP is directly required for melanoma cells to metastasize, as cells deprived of MT1-MMP fail to form distant metastasis in an orthotopic mouse melanoma model. We show that MT1-MMP affects cell invasion by activating its target MMP2. Importantly, we demonstrate, for the first time, that activation of MMP2 by MT1-MMP is required to sustain RAC1 activity and promote MT1-MMP-dependent cell motility. These data highlight a novel MT1-MMP/MMP2/RAC1 signaling axis in melanoma that may represent an intriguing molecular target for the treatment of invasive melanoma.
Original language | English (US) |
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Pages (from-to) | 287-296 |
Number of pages | 10 |
Journal | Pigment Cell and Melanoma Research |
Volume | 27 |
Issue number | 2 |
DOIs | |
State | Published - Mar 2014 |
Externally published | Yes |
Keywords
- Invasion
- MMP2
- MT1-MMP
- Migration
- RAC1
ASJC Scopus subject areas
- Oncology
- Biochemistry, Genetics and Molecular Biology(all)
- Dermatology