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

Oncogene volume 41, pages 4307–4317 (2022)Cite this article

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Abstract

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.

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Fig. 1: NRP2 expression is upregulated in NEPC.
Fig. 2: NRP2 is transcriptionally repressed by AR.
Fig. 3: Knockdown of NRP2 represses the NE traits and aggressive behavior of NEPC cells.
Fig. 4: NRP2 overexpression attenuates AR signaling and promotes NE plasticity and PC cell aggressiveness.
Fig. 5: NRP2 activates STAT3 in a VEGFR2-dependent manner.
Fig. 6: NRP2 induces NE plasticity and NEPC cell growth by STAT3 and SOX2.
Fig. 7: NRP2 silencing restricts NEPC tumor growth in mice.

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References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    PubMed  Google Scholar 

  2. Aparicio A, Logothetis CJ, Maity SN. Understanding the lethal variant of prostate cancer: power of examining extremes. Cancer Discov. 2011;1:466–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Beltran H, Tomlins S, Aparicio A, Arora V, Rickman D, Ayala G, et al. Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res. 2014;20:2846–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang HT, Yao YH, Li BG, Tang Y, Chang JW, Zhang J. Neuroendocrine Prostate Cancer (NEPC) progressing from conventional prostatic adenocarcinoma: factors associated with time to development of NEPC and survival from NEPC diagnosis-a systematic review and pooled analysis. J Clin Oncol. 2014;32:3383–90.

    Article  PubMed  Google Scholar 

  5. Davies AH, Beltran H, Zoubeidi A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat Rev Urol. 2018;15:271–86.

    Article  CAS  PubMed  Google Scholar 

  6. Ellis LM. The role of neuropilins in cancer. Mol Cancer Ther. 2006;5:1099–107.

    Article  CAS  PubMed  Google Scholar 

  7. Rizzolio S, Tamagnone L. Multifaceted role of neuropilins in cancer. Curr Med Chem. 2011;18:3563–75.

    Article  CAS  PubMed  Google Scholar 

  8. Borkowetz A, Froehner M, Rauner M, Conrad S, Erdmann K, Mayr T, et al. Neuropilin-2 is an independent prognostic factor for shorter cancer-specific survival in patients with acinar adenocarcinoma of the prostate. Int J Cancer. 2020;146:2619–27.

    Article  CAS  PubMed  Google Scholar 

  9. Goel HL, Chang C, Pursell B, Leav I, Lyle S, Xi HS, et al. VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer. Cancer Discov. 2012;2:906–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Polavaram NS, Dutta S, Islam R, Bag AK, Roy S, Poitz D, et al. Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases. Bone Res. 2021;9:24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gerhauser C, Favero F, Risch T, Simon R, Feuerbach L, Assenov Y, et al. Molecular evolution of early-onset prostate cancer identifies molecular risk markers and clinical trajectories. Cancer Cell. 2018;34:996–1011.e1018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ren S, Wei GH, Liu D, Wang L, Hou Y, Zhu S, et al. Whole-genome and transcriptome sequencing of prostate cancer identify new genetic alterations driving disease progression. Eur Urol. 2018;73:322–39.

    Article  CAS  PubMed  Google Scholar 

  13. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012;44:685–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22:298–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci USA. 2019;116:11428–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cheng S, Yu X. Bioinformatics analyses of publicly available NEPCa datasets. Am J Clin Exp Urol. 2019;7:327–40.

    PubMed  PubMed Central  Google Scholar 

  18. Tsai HK, Lehrer J, Alshalalfa M, Erho N, Davicioni E, Lotan TL. Gene expression signatures of neuroendocrine prostate cancer and primary small cell prostatic carcinoma. BMC Cancer. 2017;17:759.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. van Bokhoven A, Varella-Garcia M, Korch C, Johannes WU, Smith EE, Miller HL, et al. Molecular characterization of human prostate carcinoma cell lines. Prostate 2003;57:205–25.

    Article  PubMed  CAS  Google Scholar 

  20. Tai S, Sun Y, Squires JM, Zhang H, Oh WK, Liang CZ, et al. PC3 is a cell line characteristic of prostatic small cell carcinoma. Prostate 2011;71:1668–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Huss WJ, Gregory CW, Smith GJ. Neuroendocrine cell differentiation in the CWR22 human prostate cancer xenograft: association with tumor cell proliferation prior to recurrence. Prostate 2004;60:91–97.

    Article  PubMed  Google Scholar 

  22. Sramkoski RM, Pretlow TG 2nd, Giaconia JM, Pretlow TP, Schwartz S, Sy MS, et al. A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim. 1999;35:403–9.

    Article  CAS  PubMed  Google Scholar 

  23. Bland T, Wang J, Yin L, Pu T, Li J, Gao J, et al. WLS-Wnt signaling promotes neuroendocrine prostate cancer. iScience 2021;24:101970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Roche PJ, Hoare SA, Parker MG. A consensus DNA-binding site for the androgen receptor. Mol Endocrinol. 1992;6:2229–35.

    CAS  PubMed  Google Scholar 

  25. Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012;487:239–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xu X, Huang YH, Li YJ, Cohen A, Li Z, Squires J, et al. Potential therapeutic effect of epigenetic therapy on treatment-induced neuroendocrine prostate cancer. Asian J Androl. 2017;19:686–93.

    Article  PubMed  Google Scholar 

  27. Zhang XQ, Kondrikov D, Yuan TC, Lin FF, Hansen J, Lin MF. Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion-induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells. Oncogene 2003;22:6704–16.

    Article  CAS  PubMed  Google Scholar 

  28. Gray MJ, Van Buren G, Dallas NA, Xia L, Wang X, Yang AD, et al. Therapeutic targeting of neuropilin-2 on colorectal carcinoma cells implanted in the murine liver. J Natl Cancer Inst. 2008;100:109–20.

    Article  CAS  PubMed  Google Scholar 

  29. Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69:16–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 2017;355:84–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wen Z, Zhong Z, Darnell JE Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 1995;82:241–50.

    Article  CAS  PubMed  Google Scholar 

  32. Spiotto MT, Chung TD. STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells. Prostate 2000;42:186–95.

    Article  CAS  PubMed  Google Scholar 

  33. Tolomeo M, Cascio A. The multifaced role of STAT3 in cancer and its implication for anticancer therapy. Int J Mol Sci. 2021;22:603.

    Article  PubMed Central  CAS  Google Scholar 

  34. Neufeld G, Kessler O, Herzog Y. The interaction of Neuropilin-1 and Neuropilin-2 with tyrosine-kinase receptors for VEGF. Adv Exp Med Biol. 2002;515:81–90.

    Article  CAS  PubMed  Google Scholar 

  35. Sulpice E, Plouet J, Berge M, Allanic D, Tobelem G, Merkulova-Rainon T. Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity. Blood 2008;111:2036–45.

    Article  CAS  PubMed  Google Scholar 

  36. Hahn D, Simak R, Steiner GE, Handisurya A, Susani M, Marberger M. Expression of the VEGF-receptor Flt-1 in benign, premalignant and malignant prostate tissues. J Urol. 2000;164:506–10.

    Article  CAS  PubMed  Google Scholar 

  37. Kaushal V, Mukunyadzi P, Dennis RA, Siegel ER, Johnson DE, Kohli M. Stage-specific characterization of the vascular endothelial growth factor axis in prostate cancer: expression of lymphangiogenic markers is associated with advanced-stage disease. Clin Cancer Res. 2005;11:584–93.

    Article  CAS  PubMed  Google Scholar 

  38. Jackson MW, Roberts JS, Heckford SE, Ricciardelli C, Stahl J, Choong C, et al. A potential autocrine role for vascular endothelial growth factor in prostate cancer. Cancer Res. 2002;62:854–9.

    CAS  PubMed  Google Scholar 

  39. Favier B, Alam A, Barron P, Bonnin J, Laboudie P, Fons P, et al. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood 2006;108:1243–50.

    Article  CAS  PubMed  Google Scholar 

  40. Cai H, Reed RR. Cloning and characterization of neuropilin-1-interacting protein: a PSD-95/Dlg/ZO-1 domain-containing protein that interacts with the cytoplasmic domain of neuropilin-1. J Neurosci. 1999;19:6519–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Prahst C, Heroult M, Lanahan AA, Uziel N, Kessler O, Shraga-Heled N, et al. Neuropilin-1-VEGFR-2 complexing requires the PDZ-binding domain of neuropilin-1. J Biol Chem. 2008;283:25110–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ren X, Duan L, He Q, Zhang Z, Zhou Y, Wu D, et al. Identification of niclosamide as a new small-molecule inhibitor of the STAT3 signaling pathway. ACS Med Chem Lett. 2010;1:454–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45:D362–D368.

    Article  CAS  PubMed  Google Scholar 

  44. Bishop JL, Thaper D, Vahid S, Davies A, Ketola K, Kuruma H, et al. The master neural transcription factor BRN2 Is an androgen receptor-suppressed driver of neuroendocrine differentiation in prostate cancer. Cancer Discov. 2017;7:54–71.

    Article  CAS  PubMed  Google Scholar 

  45. Foshay KM, Gallicano GI. Regulation of Sox2 by STAT3 initiates commitment to the neural precursor cell fate. Stem Cells Dev. 2008;17:269–78.

    Article  CAS  PubMed  Google Scholar 

  46. Zhu H, Chang LL, Yan FJ, Hu Y, Zeng CM, Zhou TY, et al. AKR1C1 activates STAT3 to promote the metastasis of non-small cell lung cancer. Theranostics 2018;8:676–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhao D, Pan C, Sun J, Gilbert C, Drews-Elger K, Azzam DJ, et al. VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2. Oncogene 2015;34:3107–19.

    Article  CAS  PubMed  Google Scholar 

  48. Tse BWC, Volpert M, Ratther E, Stylianou N, Nouri M, McGowan K, et al. Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality. Oncogene 2017;36:3417–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gritsina G, Gao WQ, Yu J. Transcriptional repression by androgen receptor: roles in castration-resistant prostate cancer. Asian J Androl. 2019;21:215–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu Y, Horn JL, Banda K, Goodman AZ, Lim Y, Jana S, et al. The androgen receptor regulates a druggable translational regulon in advanced prostate cancer. Sci Transl Med. 2019;11:eaaw4993.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Tam KJ, Dalal K, Hsing M, Cheng CW, Khosravi S, Yenki P, et al. Androgen receptor transcriptionally regulates semaphorin 3C in a GATA2-dependent manner. Oncotarget 2017;8:9617–33.

    Article  PubMed  Google Scholar 

  52. Lajoie BR, Dekker J, Kaplan N. The Hitchhiker’s guide to Hi-C analysis: practical guidelines. Methods 2015;72:65–75.

    Article  CAS  PubMed  Google Scholar 

  53. Khoury A, Achinger-Kawecka J, Bert SA, Smith GC, French HJ, Luu PL, et al. Constitutively bound CTCF sites maintain 3D chromatin architecture and long-range epigenetically regulated domains. Nat Commun. 2020;11:54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Taberlay PC, Achinger-Kawecka J, Lun AT, Buske FA, Sabir K, Gould CM, et al. Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations. Genome Res. 2016;26:719–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dutta S, Polavaram NS, Islam R, Bhattacharya S, Bodas S, Mayr T, et al. Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer. Oncogene 2022;41:3747–60.

    Article  CAS  PubMed  Google Scholar 

  56. Labrecque MP, Coleman IM, Brown LG, True LD, Kollath L, Lakely B, et al. Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer. J Clin Investig. 2019;129:4492–505.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Giger RJ, Urquhart ER, Gillespie SK, Levengood DV, Ginty DD, Kolodkin AL. Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity. Neuron 1998;21:1079–92.

    Article  CAS  PubMed  Google Scholar 

  58. Potiron VA, Sharma G, Nasarre P, Clarhaut JA, Augustin HG, Gemmill RM, et al. Semaphorin SEMA3F affects multiple signaling pathways in lung cancer cells. Cancer Res. 2007;67:8708–15.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Department of Defense Prostate Cancer Research Program grant W81XWH-19-1-0279, NIH/NCI grant R37CA233658, and WSU startup funding to B.J.W. We thank Yidi Xu (Washington State University) for providing technical assistance, Mahul Amin (Cedars-Sinai Medical Center) for providing NEPC clinical samples, and Gary Mawyer for editorial assistance.

Author information

Author notes

  1. Jingjing Li

    Present address: Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China

  2. Lijuan Yin

    Present address: Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China

  3. These authors contributed equally: Jing Wang, Jingjing Li.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA

    Jing Wang, Jingjing Li, Tianjie Pu, Jing Wei & Boyang Jason Wu

  2. Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Lijuan Yin

  3. Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA

    Varsha Karthikeyan

  4. Department of Integrative Biology, School of Life Sciences, College of Science, Oregon State University, Corvallis, OR, 97331, USA

    Varsha Karthikeyan

  5. Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan, 11217, Republic of China

    Tzu-Ping Lin

  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

    Tzu-Ping Lin

  7. Department of Urologic Surgery, University of California Davis, Sacramento, CA, 95817, USA

    Allen C. Gao

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Contributions

B.J.W. conceived the study. J. Wang, J.L., and B.J.W. designed the experiments. J. Wang, J.L., L.Y., T.P. J. Wei, and V.K. performed the experiments. J. Wang, J.L., L.Y., and B.J.W. analyzed the data. T.-P.L. provided human CRPC tissue microarrays. A.C.G. provided control and ENZR C4-2B cells. B.J.W. wrote the manuscript, supervised the study, and acquired funding.

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Correspondence to Boyang Jason Wu.

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Wang, J., Li, J., Yin, L. et al. Neuropilin-2 promotes lineage plasticity and progression to neuroendocrine prostate cancer. Oncogene 41, 4307–4317 (2022). https://doi.org/10.1038/s41388-022-02437-0

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