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Neuropilin-2 promotes lineage plasticity and progression to neuroendocrine prostate cancer

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机构： [1]Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA. [2]Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. [3]Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA. [4]Department of Integrative Biology, School of Life Sciences, College of Science, Oregon State University, Corvallis, OR 97331, USA. [5]Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan 11217, Republic of China. [6]Department of Urology, School of Medicine and Shu-Tien Urological Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan 11221, Republic of China. [7]Department of Urologic Surgery, University of California Davis, Sacramento, CA 95817, USA. [8]Present address: Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. [9]Present address: Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

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Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer, is characterized by loss of AR signaling and resulting resistance to AR-targeted therapy during neuroendocrine transdifferentiation, for which the molecular mechanisms remain unclear. Here, we report that neuropilin 2 (NRP2) is upregulated in both de novo and therapy-induced NEPC, which induces neuroendocrine markers, neuroendocrine cell morphology, and NEPC cell aggressive behavior. NRP2 silencing restricted NEPC tumor xenograft growth. Mechanistically, NRP2 engages in reciprocal crosstalk with AR, where NRP2 is transcriptionally inhibited by AR, and in turn suppresses AR signaling by downregulating the AR transcriptional program and confers resistance to enzalutamide. Moreover, NRP2 physically interacts with VEGFR2 through the intracellular SEA domain to activate STAT3 phosphorylation and subsequently SOX2, thus driving NEPC differentiation and growth. Collectively, these results characterize NRP2 as a driver of NEPC and suggest NRP2 as a potential therapeutic target in NEPC.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.

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大类 | 1 区

医学

小类 | 1 区遗传学 1 区生化与分子生物学 1 区肿瘤学 2 区细胞生物学

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大类 | 1 区

医学

小类 | 1 区生化与分子生物学 1 区遗传学 2 区细胞生物学 2 区肿瘤学

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第一作者机构： [1]Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA.

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