Abstract

The AlphaV-Beta3 Integrin/NgR2 Complex is Up-regulated in Prostate Cancer Cell-derived EVs and Patient-derived EVs and Represents a Promising Therapeutic Target

Anna Testa, Medical Resident, Thomas Jefferson University

The AlphaV-Beta3 integrin, known to promote growth and metastasis of several types of cancer, is highly expressed in neuroendocrine prostate cancer (NEPrCa). PrCa cell-derived small extracellular vesicles (sEVs) expressing AlphaV-Beta3 contribute to NEPrCa differentiation in recipient cells. AlphaV-Beta3 integrin upregulates NgR2, a glycosylphosphatidylinositol-anchored receptor, in NEPrCa cells. By investigating the impact of AlphaV-Beta3 expression in sEVs on downstream protein expression via proteomic analysis, we demonstrate that AlphaV-Beta3+ sEVs also show an up-regulation in NgR2 expression; furthermore, a down-regulation of typical effectors involved in apoptosis and necrosis and an up-regulation of tumor cell survival factors emerge, as compared to control sEVs. We also show that EVs isolated from metastatic castrate-resistant prostate cancer (mCRPC) patients plasma are enriched in AlphaV-Beta3 and NgR2. sEVs used in these experiments were isolated by density gradient and characterized by nanoparticle tracking analysis and immunoblotting. Additionally, by testing the effect of AlphaV-Beta3 inhibition in NEPrCa-patient derived xenografts (PDXs) using LM609, a monoclonal antibody (mAb) specific for AlphaV-Beta3, we demonstrate a significant reduction of tumor volume and weight in NE-PDXs carrying mice upon treatment with LM609. Our findings suggest that AlphaV-Beta3 integrin and NgR2 are key components of NEPrCa progression and represent a promising therapeutic target both in vitro and in vivo.