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Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer [ChIP-seq]

ABSTRACT: Our study using prostate cancer tissues and cell lines observed that neuropilin-2 (NRP2) can translocate to the nucleus of advanced prostate cancer cells. NRP2 is present in the nuclear membrane and near to the nuclear pore. To understand the functions of nuclear NRP2 in prostate cancer, we have performed NRP2-specific chromatin immunoprecipitation DNA-sequencing (ChIP-seq) in prostate cancer cell. Our results showed NRP2 forms a complex with transcription factors and pore proteins, which helps the transcription factors to be recruited at the promoter regions of genes. The nature of the interaction between NRP2-transcription factors is dynamic and depends on various physiological and pathological conditions. The ChIP-seq was carried in duplicate using adenocarcinoma cell lines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205148 | GEO | 2022/06/03

REPOSITORIES: GEO

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Therapeutic Blocking of VEGF Binding to Neuropilin-2 Diminishes PD-L1 Expression to Activate Anti-Tumor Immunity in Prostate Cancer

Project description:Prostate cancers (PC) are largely unresponsive to immune checkpoint inhibitors and there is strong evidence that PD-L1 expression itself must be inhibited to activate anti-tumor immunity. Here, we report that neuropilin-2 (NRP2), which functions as a VEGF receptor on tumor cells, is an attractive target to activate anti-tumor immunity in prostate cancer because we demonstrate that VEGF/NRP2 signaling sustains PD-L1 expression. NRP2 depletion increased T cell activation in vitro. Inhibition of the binding of VEGF to NRP2 using a mouse specific anti-NRP2 mAb in a syngeneic model of prostate cancer that is resistant to checkpoint inhibition resulted in significant necrosis and tumor regression compared to both an anti-PD-L1 mAb and control IgG. This therapy also decreased tumor PD-L1 expression and increased immune cell infiltration. We also observed that the NRP2, VEGF-A, and VEGF-C genes are amplified in metastatic castration resistant and neuroendocrine prostate cancer (NEPC) and that NRP2high PD-L1high population in metastatic tumors had a significantly lower AR and higher NEPC scores than other populations. Therapeutic inhibition of VEGF binding to human NRP2 with a high affinity humanized mAb, which is suitable for clinical use, in organoids derived from NEPC patients also diminished PD-L1 expression and caused a significant increase in immune-mediated tumor cell killing consistent with the animal studies. These findings provide justification for the initiation of clinical trials using this novel function-blocking NRP2 mAb in prostate cancer, especially for patients with aggressive primary and metastatic cancers, where blocking NRP2-VEGF signaling shows potential in mitigating the morbidity and mortality associated with these cancers.

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A proteomics approach to isolating neuropilin-dependent α5 integrin trafficking pathways: neuropilin 1 and 2 co-traffic α5 integrin through endosomal p120RasGAP to promote polarised fibronectin fibrillogenesis in endothelial cells

Project description:Integrin trafficking to and from membrane adhesions is a crucial mechanism that dictates many aspects of a cell’s behaviour, including motility, polarisation, and invasion. In endothelial cells (ECs), the intracellular traffic of α5-integrin is regulated by both neuropilin 1 (NRP1) and neuropilin 2 (NRP2), yet the redundancies in function between these co-receptors remain unclear. Moreover, the endocytic complexes that participate in NRP-directed-traffic remain poorly annotated. Here we identify an important role for the GTPase-activating protein p120RasGAP in ECs, promoting the recycling of α5-integrin from early endosomes. Mechanistically, p120RasGAP enables transit of endocytosed α5-integrin-NRP1-NRP2 complexes to Rab11+ recycling endosomes, promoting cell polarisation and fibronectin (FN) fibrillogenesis. Silencing of both NRP receptors, or p120RasGAP, resulted in the accumulation of α5-integrin in early endosomes, a loss of α5-integrin from surface adhesions, and attenuated EC polarisation. Endothelial-specific deletion of both NRP1 and NRP2 in the postnatal retina recapitulated our in vitro findings, severely impairing FN fibrillogenesis and polarised sprouting. Our data assign an essential role for p120RasGAP during integrin traffic in ECs and support a hypothesis that NRP receptors co-traffic internalised cargoes. Importantly, we utilise comparative proteomics analyses to, for the first time, isolate a comprehensive map of NRP1-dependent and NRP2-dependent-α5-integrin interactions in ECs.

2024-05-20 | PXD051778 | Pride

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2018-07-26 | PXD007185 | Pride

Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer [RNA-seq]

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2018-08-22 | GSE103637 | GEO

Neuropilin-1+ vs. Neuropilin-1- CD8+ T cells from Plasmodium berghei ANKA-infected mice

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Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer

Project description:Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer

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Neuropilin-1 is Required for the Suppressive Function of Human Regulatory T Cells

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2019-01-01 | GSE106932 | GEO

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