253 Targeting tumour vascularisation through endothelial-specific Sox9 deletion reduces melanoma metastasis through reduction of vascularisation, changing melanoma gene expression pattern

Abstract

The formation of new blood vessels from pre-existing ones, known as angiogenesis, is crucial in development and adulthood. One of the critical players is the zinc-dependent matrixmetalloproteinase MMP14. Complete loss of the protease underscored its importance in vivo as mice died within three weeks after birth due to several severe developmental defects, some due to impaired angiogenesis. To enable the analysis of the specific function of endothelial MMP14 in skin physiology and pathology, we generated mice with constitutive endothelial cell-specific deletion of MMP14 (MMP14 EC-/-). These mice developed and bred with no alterations in tissue vascularization. On the contrary, in pathological conditions, as in melanoma growth, loss of endothelial MMP14 resulted in reduced tumor growth and metastasis. While tumor vessel density and distribution were unaltered, vessel permeability was decreased. Analysis of underlying mechanisms that regulate vessel permeability revealed increased vessel coverage by pericytes. Moreover, VE-cadherin expression was enhanced, while eNOS expression and nitric oxide production in MMP14 EC-/endothelial cells were significantly reduced. Altogether, we show that MMP14 in endothelial cells, although it does not play a significant role during development, orchestrates several events in endothelial cells that control tumor vessel function. These data provide a better understanding of the role of endothelial cell-MMP14 and the potential use of targeting MMP14 as a therapeutic approach in melanoma.