Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

MAOA promotes prostate cancer cell perineural invasion through SEMA3C/PlexinA2/NRP1–cMET signaling

Abstract

Perineural invasion (PNI), a pathologic feature defined as cancer cell invasion in, around, and through nerves, is an indicator of poor prognosis and survival in prostate cancer (PC). Despite widespread recognition of the clinical significance of PNI, the molecular mechanisms are largely unknown. Here, we report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PNI in PC. MAOA promotes PNI of PC cells in vitro and tumor innervation in an orthotopic xenograft model. Mechanistically, MAOA activates SEMA3C in a Twist1-dependent transcriptional manner, which in turn stimulates cMET to facilitate PNI via autocrine or paracrine interaction with coactivated PlexinA2 and NRP1. Furthermore, MAOA inhibitor treatment effectively reduces PNI of PC cells in vitro and tumor-infiltrating nerve fiber density along with suppressed xenograft tumor growth and progression in mice. Collectively, these findings characterize the contribution of MAOA to the pathogenesis of PNI and provide a rationale for using MAOA inhibitors as a targeted treatment for PNI in PC.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Elevated MAOA expression is associated with PNI in PC.
Fig. 2: MAOA promotes PNI of PC cells in cancer–nerve cell co-cultures.
Fig. 3: MAOA induces PNI of PC cells through activation of class 3 semaphorin signaling.
Fig. 4: The SEMA3C/PlexnA2/NRP1 triad mediates MAOA’s effect on PNI of PC cells in a cMET-dependent manner.
Fig. 5: MAOA activates SEMA3C directly through Twist1 in PC cells.
Fig. 6: MAOA enhances tumor innervation during prostate tumor growth and progression in mice.
Fig. 7: Pharmacological inhibition of MAOA reduces PNI and tumor infiltration by nerves in PC.

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Article  PubMed  Google Scholar 

  2. Deng X, He G, Liu J, Luo F, Peng X, Tang S, et al. Recent advances in bone-targeted therapies of metastatic prostate cancer. Cancer Treat Rev. 2014;40:730–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer: a review of the literature. Cancer. 2009;115:3379–91.

    CAS  PubMed  Google Scholar 

  4. Maru N, Ohori M, Kattan MW, Scardino PT, Wheeler TM. Prognostic significance of the diameter of perineural invasion in radical prostatectomy specimens. Hum Pathol. 2001;32:828–33.

    CAS  PubMed  Google Scholar 

  5. Villers A, McNeal JE, Redwine EA, Freiha FS, Stamey TA. The role of perineural space invasion in the local spread of prostatic adenocarcinoma. J Urol. 1989;142:763–8.

    CAS  PubMed  Google Scholar 

  6. Kraus RD, Barsky A, Ji L, Garcia Santos PM, Cheng N, Groshen S, et al. The perineural invasion paradox: is perineural invasion an independent prognostic indicator of biochemical recurrence risk in patients with pT2N0R0 prostate cancer? A multi-institutional study. Adv Radiat Oncol. 2019;4:96–102.

    PubMed  Google Scholar 

  7. DeLancey JO, Wood DP Jr., He C, Montgomery JS, Weizer AZ, Miller DC, et al. Evidence of perineural invasion on prostate biopsy specimen and survival after radical prostatectomy. Urology. 2013;81:354–7.

    PubMed  Google Scholar 

  8. Ciftci S, Yilmaz H, Ciftci E, Simsek E, Ustuner M, Yavuz U, et al. Perineural invasion in prostate biopsy specimens is associated with increased bone metastasis in prostate cancer. Prostate. 2015;75:1783–9.

    PubMed  Google Scholar 

  9. Bakst RL, Wong RJ. Mechanisms of perineural invasion. J Neurol Surg B Skull Base. 2016;77:96–106.

    PubMed  PubMed Central  Google Scholar 

  10. Jobling P, Pundavela J, Oliveira SM, Roselli S, Walker MM, Hondermarck H. Nerve-cancer cell cross-talk: a novel promoter of tumor progression. Cancer Res. 2015;75:1777–81.

    CAS  PubMed  Google Scholar 

  11. Ding Y, He D, Florentin D, Frolov A, Hilsenbeck S, Ittmann M, et al. Semaphorin 4F as a critical regulator of neuroepithelial interactions and a biomarker of aggressive prostate cancer. Clin Cancer Res. 2013;19:6101–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Binmadi NO, Yang YH, Zhou H, Proia P, Lin YL, De Paula AM, et al. Plexin-B1 and semaphorin 4D cooperate to promote perineural invasion in a RhoA/ROK-dependent manner. Am J Pathol. 2012;180:1232–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kruger RP, Aurandt J, Guan KL. Semaphorins command cells to move. Nat Rev Mol Cell Biol. 2005;6:789–800.

    CAS  PubMed  Google Scholar 

  14. Bortolato M, Chen K, Shih JC. Monoamine oxidase inactivation: from pathophysiology to therapeutics. Adv drug Deliv Rev. 2008;60:1527–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Shih JC, Chen K, Ridd MJ. Monoamine oxidase: from genes to behavior. Annu Rev Neurosci. 1999;22:197–217.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. True L, Coleman I, Hawley S, Huang CY, Gifford D, Coleman R, et al. A molecular correlate to the Gleason grading system for prostate adenocarcinoma. Proc Natl Acad Sci USA. 2006;103:10991–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu JB, Shao C, Li X, Li Q, Hu P, Shi C, et al. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. J Clin Invest. 2014;124:2891–908.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wu JB, Yin L, Shi C, Li Q, Duan P, Huang JM, et al. MAOA-dependent activation of Shh-IL6-RANKL signaling network promotes prostate cancer metastasis by engaging tumor-stromal cell interactions. Cancer Cell. 2017;31:368–82.

    CAS  PubMed  Google Scholar 

  19. Flamand V, Zhao H, Peehl DM. Targeting monoamine oxidase A in advanced prostate cancer. J Cancer Res Clin Oncol. 2010;136:1761–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Westerink RH, Ewing AG. The PC12 cell as model for neurosecretion. Acta Physiol (Oxf). 2008;192:273–85.

    CAS  Google Scholar 

  21. Chen W, Mi R, Haughey N, Oz M, Hoke A. Immortalization and characterization of a nociceptive dorsal root ganglion sensory neuronal line. J Peripher Nerv Syst. 2007;12:121–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Saloman JL, Albers KM, Rhim AD, Davis BM. Can stopping nerves, stop cancer? Trends Neurosci. 2016;39:880–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Pundavela J, Demont Y, Jobling P, Lincz LF, Roselli S, Thorne RF, et al. ProNGF correlates with Gleason score and is a potential driver of nerve infiltration in prostate cancer. Am J Pathol. 2014;184:3156–62.

    CAS  PubMed  Google Scholar 

  24. Herman JG, Meadows GG. Increased class 3 semaphorin expression modulates the invasive and adhesive properties of prostate cancer cells. Int J Oncol. 2007;30:1231–8.

    CAS  PubMed  Google Scholar 

  25. Tam KJ, Hui DHF, Lee WW, Dong M, Tombe T, Jiao IZF, et al. Semaphorin 3 C drives epithelial-to-mesenchymal transition, invasiveness, and stem-like characteristics in prostate cells. Sci Rep. 2017;7:11501.

    PubMed  PubMed Central  Google Scholar 

  26. 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.

    PubMed  Google Scholar 

  27. Peacock JW, Takeuchi A, Hayashi N, Liu L, Tam KJ, Al Nakouzi N, et al. SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1. EMBO Mol Med. 2018;10:219–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. He S, Chen CH, Chernichenko N, He S, Bakst RL, Barajas F, et al. GFRalpha1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc Natl Acad Sci USA. 2014;111:E2008–2017.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Swiercz JM, Kuner R, Offermanns S. Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol. 2004;165:869–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, et al. The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol. 2002;4:720–4.

    CAS  PubMed  Google Scholar 

  31. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927–39.

    CAS  PubMed  Google Scholar 

  32. Carden MJ, Trojanowski JQ, Schlaepfer WW, Lee VM. Two-stage expression of neurofilament polypeptides during rat neurogenesis with early establishment of adult phosphorylation patterns. J Neurosci. 1987;7:3489–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, et al. Autonomic nerve development contributes to prostate cancer progression. Science. 2013;341:1236361.

    PubMed  Google Scholar 

  34. Zhang D, Park D, Zhong Y, Lu Y, Rycaj K, Gong S, et al. Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer. Nat Commun. 2016;7:10798.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Chilton JK. Molecular mechanisms of axon guidance. Developmental Biol. 2006;292:13–24.

    CAS  Google Scholar 

  36. Ayala GE, Dai H, Powell M, Li R, Ding Y, Wheeler TM, et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin Cancer Res. 2008;14:7593–603.

    CAS  PubMed  Google Scholar 

  37. Chauvet S, Cohen S, Yoshida Y, Fekrane L, Livet J, Gayet O, et al. Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development. Neuron. 2007;56:807–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Li J, Pu T, Yin L, Li Q, Liao CP, Wu BJ. MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness. Oncogene. 2020;39:3305–21.

  39. Parra LM, Zou Y. Sonic hedgehog induces response of commissural axons to Semaphorin repulsion during midline crossing. Nat Neurosci. 2010;13:29–35.

    CAS  PubMed  Google Scholar 

  40. Khatiwada P, Kannan A, Malla M, Dreier M, Shemshedini L. Androgen up-regulation of Twist1 gene expression is mediated by ETV1. PeerJ. 2020;8:e8921.

    PubMed  PubMed Central  Google Scholar 

  41. Eide T, Ramberg H, Glackin C, Tindall D, Tasken KA. TWIST1, A novel androgen-regulated gene, is a target for NKX3-1 in prostate cancer cells. Cancer Cell Int. 2013;13:4.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Gaur S, Gross ME, Liao CP, Qian B, Shih JC. Effect of monoamine oxidase A (MAOA) inhibitors on androgen-sensitive and castration-resistant prostate cancer cells. Prostate. 2019;79:667–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G. Targeting MET in cancer: rationale and progress. Nat Rev Cancer. 2012;12:89–103.

    CAS  PubMed  Google Scholar 

  44. Knudsen BS, Gmyrek GA, Inra J, Scherr DS, Vaughan ED, Nanus DM, et al. High expression of the Met receptor in prostate cancer metastasis to bone. Urology. 2002;60:1113–7.

    PubMed  Google Scholar 

  45. Ko KR, Lee J, Lee D, Nho B, Kim S. Hepatocyte growth factor (HGF) promotes peripheral nerve regeneration by activating repair Schwann cells. Sci Rep. 2018;8:8316.

    PubMed  PubMed Central  Google Scholar 

  46. Wong V, Glass DJ, Arriaga R, Yancopoulos GD, Lindsay RM, Conn G. Hepatocyte growth factor promotes motor neuron survival and synergizes with ciliary neurotrophic factor. J Biol Chem. 1997;272:5187–91.

    CAS  PubMed  Google Scholar 

  47. Huyett P, Gilbert M, Liu L, Ferris RL, Kim S. A model for perineural invasion in head and neck squamous cell Carcinoma. J Vis Exp. 2017;119:55043.

Download references

Acknowledgements

We thank Gina Chu (Cedars-Sinai Medical Center) for technical help, Leland W.K. Chung (Cedars-Sinai Medical Center) for comprehensive support of this study, and Gary Mawyer for editorial assistance. This work was supported by DOD Prostate Cancer Research Program grants W81XWH-15-1-0493 and W81XWH-19-1-0279, NIH/NCI grant R37CA233658, and the WSU startup fund to BJW.

Author information

Authors and Affiliations

Authors

Contributions

Conception and design: BJW. Development of methodology: LY, JL, BJW. Acquisition of data: LY, JL, J Wang, TP, J Wei, QL, BJW. Analysis and interpretation of data: LY, JL, J Wang, T Pu, QL, BJW. Writing of the manuscript: BJW. Study supervision: BJW.

Corresponding author

Correspondence to Boyang Jason Wu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yin, L., Li, J., Wang, J. et al. MAOA promotes prostate cancer cell perineural invasion through SEMA3C/PlexinA2/NRP1–cMET signaling. Oncogene 40, 1362–1374 (2021). https://doi.org/10.1038/s41388-020-01615-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-020-01615-2

This article is cited by

Search

Quick links