Neuropilin-2 axis in regulating secretory phenotype of neuroendocrine-like prostate cancer cells and its implication in therapy resistance

Neuroendocrine (NE)-like tumors secrete various signaling molecules to establish paracrine communication within the tumor milieu and to create a therapy-resistant environment. It is important to identify molecular mediators that regulate this secretory phenotype in NE-like cancer. The current study highlights the importance of a cell surface molecule, Neuropilin-2 (NRP2), for the secretory function of NE-like prostate cancer (PCa). Our analysis on different patient cohorts suggests that NRP2 is high in NE-like PCa. We have developed cell line models to investigate NRP2’s role in NE-like PCa. Our bioinformatics, mass spectrometry, cytokine array, and other supporting experiments reveal that NRP2 regulates robust secretory phenotype in NE-like PCa and controls the secretion of factors promoting cancer cell survival. Depletion of NRP2 reduces the secretion of these factors and makes resistant cancer cells sensitive to chemotherapy in vitro and in vivo. Therefore, targeting NRP2 can revert cellular secretion and sensitize PCa cells toward therapy. [Display omitted] •NRP2 is highly expressed in NE-like prostate cancer•NRP2 regulates the fusion of secretory vesicles to plasma membrane•The secretion of several cytokines, including IL-8, is regulated by NRP2•NRP2-depletion from NE-like cells sensitizes adjacent adenocarcinoma to chemotherapy Islam et al. observe high expression of a cell surface receptor, neuropilin-2 (NRP2), in neuroendocrine-like prostate cancer. NRP2 regulates the secretion of cytokines by facilitating the fusion of secretory vesicles to cell membrane. The secretory products protect not only the neuroendocrine cells but also the adjacent adenocarcinoma from chemotherapies.