Abstract 8: The protein tyrosine phosphatase DEP-1/PTPRJ is an essential promoter of vascular permeability, angiogenesis and tumor progression

Abstract Angiogenesis and increased vessel permeability play key roles during tumor growth and cancer progression. Therefore, much current effort in the field aims at understanding the molecular mechanisms underlying the formation and remodeling of blood vessels as a way to identify new approaches to harness these processes. In this context, we have been focusing our efforts on the protein tyrosine phosphatase DEP-1 (also named PTPRJ or CD148), which was initially identified as a negative regulator of cell proliferation and VEGFR2 phosphorylation when highly expressed in quiescent endothelial cells. However, using an RNAi knockdown approach, we demonstrated for the first time that through its ability to dephosphorylate the Src inhibitory Y529, DEP-1 was also a positive regulator of Src activation in VEGF-stimulated endothelial cells. As Src plays key roles in the promotion of angiogenesis and vascular permeability, we further demonstrated that DEP-1 was indeed a promoter of these vascular functions in vitro, and that the tyrosine phosphorylation of its C-terminal tail, allowing Src interaction and activation, was required for this. Interestingly, the catalytic inactivation of DEP-1 in mice led to increased endothelial cell proliferation, but also disorganized vascular structures, in contrast with the apparent absence of phenotype in DEP-1 knock-out (KO) mice models. In this study, we evaluated the biological consequences of the loss of DEP-1 expression on normal and pathological angiogenesis using a complete KO mouse model. We first confirmed that DEP-1 was required for Src activation and the phosphorylation of its substrates VE-cadherin and FAK in mice lung lysates upon systemic VEGF stimulation. Consistent with these observations, VEGF-induced vascular leakage was abrogated in the DEP-1 KO mice, as determined using a modified Miles assay. Capillary formation from mouse aortic rings ex vivo and in Matrigel plugs was also impaired, demonstrating the key positive role of DEP-1 in permeability and angiogenesis. Ischemia-induced angiogenesis was also deficient in KO mice, as demonstrated by reduced limb blood flow and capillary formation in a hind limb ischemia model. To assess tumor-associated angiogenesis, the highly metastatic Mvt-1 mouse mammary tumor cells were orthotopically injected in WT and DEP-1 KO mice. The growth of tumors in DEP-1 KO mice was reduced by about 50% compared to those grown in WT animals, due to inhibition of tumor angiogenesis. As tumor-associated and leaky blood vessels contribute to dissemination of cancer cells, a 50-60% decrease in the number and size of spontaneous and experimental metastases were also observed in the lungs of DEP-1 KO mice. Altogether, these results demonstrate for the first time that DEP-1 is an essential driver of VEGF-dependent Src activation, permeability, and angiogenesis in vivo, therefore acting as a promoter of tumor cell growth and dissemination. Citation Format: Patrick Fournier, Sylvie Dussault, Alfredo Fusco, Alain Rivard, Isabelle Royal. The protein tyrosine phosphatase DEP-1/PTPRJ is an essential promoter of vascular permeability, angiogenesis and tumor progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 8. doi:10.1158/1538-7445.AM2014-8

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