Intercellular Communication in Prostate Cancer Progression

Therapeutic approaches aimed at curing prostate cancer (PrCa) are only partially successful given the occurrence of highly metastatic phenotypes, such as neuroendocrine PrCa (NEPC). Through a series of investigations based on in vitro methods [isolation of sEVs (small extracellular vesicles), proteomics, organoid cultures and motility assays] and analysis of human NEPC specimens and mouse models of NEPC, we have collected considerable novel data to support our hypothesis that pathways activated by the αVβ3 integrin are promising therapeutic targets for NEPC. While absent in prostate adenocarcinoma, αVβ3 expression is increased during PrCa progression, is released into the tumor microenvironment (TME) through sEVs and reprograms recipient cells toward an aggressive NE phenotype. Our data also show that αVβ3 up-regulates NgR2 (Nogo-66 receptor homolog 1) known to be increased in human NEPC; NgR2 is associated with αVβ3, stimulates adhesion of PrCa cells to αVβ3 ligands, is expressed in sEVs, promotes tumor growth and expression of NE markers. In addition, the αVβ3 integrin and NgR2 are found in metastatic prostate cancer patients’ circulating sEVs which have and support a highly adhesive phenotype of monocytes. Our analysis of αVβ3+ sEVs identifies NgR2 as a main effector of αVβ3 capable of reprogramming cells toward a NE phenotype. These results offer a strong premise in support of our innovative hypothesis that NgR2 may influence the functions of αVβ3-bearing sEVs in target cells, and cancer progression toward a NE phenotype. To test our hypothesis that transfer of the αVβ3 integrin and NgR2 from cancer cells to the tumor and to the TME promotes NEPC, we propose three specific aims that utilize innovative approaches and models. AIM 1: In collaboration with Project 2, we will test a causal role of NgR2 in sEVs in tumor growth, NE differentiation and metastasis upon sEV transfer, using a SILAC-based proteomics analysis. AIM 2: We will analyze the active state of αVβ3 in sEVs using NanoView Biosciences ExoView-chips coated on the basis of its interaction with NgR2. We will also determine if αVβ3 or NgR2 are expressed in sEVs in human plasma specimens and test if αVβ3 is active. Finally, we will investigate whether αVβ3 integrin and NgR2 increase RhoA expression as well as JAK/STAT activation in recipient cells upon sEV delivery, and test whether these pathways are needed for the NE-promoting activity. AIM 3: We will determine a) the relationship between IL-4 production and αVβ3 and NgR2 expression in human PrCa tumors as they progress to the NE state b) if the expression of αVβ3 and NgR2 in PrCa sEVs plays a key role in their effects on T cells, monocytes and prostate epithelial cells in vitro c) the impact of αVβ3 and NgR2 on tumor growth and immunity in vivo in mouse PrCa models. Because there are currently no effective therapeutic approaches for NEPC, we expect that our proposal will validate new targets and enable the design of new therapies for this cancer. Project Number: 1P01CA298993-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Lucia Languino | Institution: THOMAS JEFFERSON UNIVERSITY, PHILADELPHIA, PA | Award Amount: $416,992 | Activity Code: P01 | Study Section: Special Emphasis Panel[ZRG1 CTH-W (45)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11265631