Abstract 894: Heparanase-induced shedding of syndecan-1 promotes cancer cell invasion : prevention by inhibitory synstatin peptide

Abstract

Abstract Syndecan-1 (Sdc1, CD138) is highly expressed in multiple myeloma (MM). Heparanase (HPSE), an enzyme that cleaves heparan sulfate (HS) chains on Sdc1, induces shedding of the Sdc1 ectodomain; this is associated with poor prognosis in this disease. However, the link between Sdc1 shedding and poor prognosis remains unclear. We now show that HPSE-induced shed Sdc1 (sSdc1) engages α4β1 integrin (VLA-4) and vascular endothelial cell growth factor receptor-2 (VEGFR2) to form a ternary receptor complex on the cell surface. This coupling of VEGFR2 to clusters of VLA-4 via sSdc1 leads to autoactivation of VEGFR2 and the subsequent activation of protein kinase A (PKA) bound to the VEGFR2 cytoplasmic domain. PKA activation proceeds via VEGFR2-mediated stimulation of the G-protein coupled cytokine receptor CXCR4 and the subsequent generation of cAMP by its activation of adenylate cyclase 7. This mechanism is prevented by SSTNVEGFR2, a peptide that competes for the VEGFR2 docking site in the Sdc1 ectodomain, thereby disrupting VEGFR2 binding to sSdc1. VLA-4 has been shown to mediate the polarized invasion of a variety of cells due to α4 integrin phosphorylation on Ser988 by PKA, followed by Rac GTPase activation, a process that is restricted to the leading edge of the cell. But how this is confined at the leading edge is wholly unknown. We find that HPSE-mediated shedding of Sdc1 promotes an invasive phenotype by re-localizing VLA-4 and VEGFR2 to the leading edge of migrating myeloma cells as well as human T-acute lymphoblastic leukemia, melanoma, and endothelial cells where VEGFR2-dependent PKA activation causes α4 integrin phosphorylation. These results reveal a novel mechanism in which the expression of HPSE, acting by causing Sdc1 shedding, potentially regulates angiogenesis and the extravasation and invasion of cancer cells and identifies SSTNVEGFR2 as a promising cancer therapeutic. Citation Format: Oisun Jung, Alan Rapraeger. Heparanase-induced shedding of syndecan-1 promotes cancer cell invasion : prevention by inhibitory synstatin peptide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 894. doi:10.1158/1538-7445.AM2017-894