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