Landscape of prostate-specific membrane antigen heterogeneity and regulation in AR-positive and AR-negative metastatic prostate cancer Journal Article

   


Authors: Bakht, M. K.; Yamada, Y.; Ku, S. Y.; Venkadakrishnan, V. B.; Korsen, J. A.; Kalidindi, T. M.; Mizuno, K.; Ahn, S. H.; Seo, J. H.; Garcia, M. M.; Khani, F.; Elemento, O.; Long, H. W.; Chaglassian, A.; Pillarsetty, N.; Lewis, J. S.; Freedman, M.; Belanger, A. P.; Nguyen, Q. D.; Beltran, H.
Article Title: Landscape of prostate-specific membrane antigen heterogeneity and regulation in AR-positive and AR-negative metastatic prostate cancer
Abstract: Tumor expression of prostate-specific membrane antigen (PSMA) is lost in 15–20% of men with castration-resistant prostate cancer (CRPC), yet the underlying mechanisms remain poorly defined. In androgen receptor (AR)-positive CRPC, we observed lower PSMA expression in liver lesions versus other sites, suggesting a role of the microenvironment in modulating PSMA. PSMA suppression was associated with promoter histone 3 lysine 27 methylation and higher levels of neutral amino acid transporters, correlating with 18F-fluciclovine uptake on positron emission tomography imaging. While PSMA is regulated by AR, we identified a subset of AR-negative CRPC with high PSMA. HOXB13 and AR co-occupancy at the PSMA enhancer and knockout models point to HOXB13 as an upstream regulator of PSMA in AR-positive and AR-negative prostate cancer. These data demonstrate how PSMA expression is differentially regulated across metastatic lesions and in the context of the AR, which may inform selection for PSMA-targeted therapies and development of complementary biomarkers. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords: immunohistochemistry; controlled study; human tissue; protein expression; human cell; genetics; nonhuman; positron emission tomography; lymph node metastasis; prostate specific antigen; animal cell; mouse; metabolism; animal tissue; gene expression; animal experiment; animal model; prostate-specific antigen; liver metastasis; prostate specific membrane antigen; prostate; immunocytochemistry; chromatin immunoprecipitation; western blotting; positron-emission tomography; immunoblotting; thin layer chromatography; liver injury; castration resistant prostate cancer; tumor microenvironment; principal component analysis; gene expression level; procedures; metastatic prostate cancer; sevoflurane; fluciclovine f 18; humans; human; male; article; prostatic neoplasms, castration-resistant; amino acid transporter; differential expression analysis; crispr-cas9 system; positron emission tomography-computed tomography; single cell rna seq; chromatin immunoprecipitation sequencing; illumina sequencing; androgen receptor negative metastatic prostate cancer; androgen receptor positive metastatic prostate cancer; bicinchoninic acid assay
Journal Title: Nature Cancer
Volume: 4
Issue: 5
ISSN: 2662-1347
Publisher: Nature Research  
Date Published: 2023-05-01
Start Page: 699
End Page: 715
Language: English
DOI: 10.1038/s43018-023-00539-6
PUBMED: 37038004
PROVIDER: scopus
PMCID: PMC10867901
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85152420783&doi=10.1038%2fs43018-023-00539-6&partnerID=40&md5=dda5dd95ae73860c92572740b411edb3
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus
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MSK Authors
  1. Nagavarakishore Pillarsetty
    134 Pillarsetty
  2. Jason S Lewis
    460 Lewis
  3. Teja Muralidhar Kalidindi
    39 Kalidindi
  4. Joshua Aaron Korsen
    12 Korsen
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