Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice

Phenotypic plasticity is a hallmark of cancer and is increasingly realized as a mechanism of resistance to androgen receptor-targeted (AR-targeted) therapy. Now that many prostate cancer (PCa) patients are treated upfront with AR-targeted agents, it is critical to identify actionable mechanisms that drive phenotypic plasticity, to prevent the emergence of resistance. We showed that loss of tristetraprolin (TTP; gene ZFP36) increased NF-κB activation, and was associated with higher rates of aggressive disease and early recurrence in primary PCa. We also examined the clinical and biological impact of ZFP36 loss with co-loss of PTEN, a known driver of PCa. Analysis of multiple independent primary PCa cohorts demonstrated that PTEN and ZFP36 co-loss was associated with increased recurrence risk. Engineering prostate-specific Zfp36 deletion in vivo induced prostatic intraepithelial neoplasia, and, with Pten codeletion, resulted in rapid progression to castration-resistant adenocarcinoma. Zfp36 loss altered the cell state driven by Pten loss, as demonstrated by enrichment of epithelial-mesenchymal transition (EMT), inflammation, TNF-α/NF-κB, and IL-6-JAK/STAT3 gene sets. Additionally, our work revealed that ZFP36 loss also induced enrichment of multiple gene sets involved in mononuclear cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor dimethylaminoparthenolide (DMAPT) induced marked therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed castration resistance.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2024-11-19
DOI
https://doi.org/10.1172/jci175680
Citations
6
Primary Topic
Prostate Cancer Treatment and Research
Type
article
Field-Weighted Citation Impact
2.51

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article

Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice

Jasmine Plummer, Christopher J. Sweeney, Shana Y. Trostel, Wilbert Zwart et al.
6 citations
Journal of Clinical Investigation
Prostate Cancer Treatment and Research
2.51
article

Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice

Jasmine Plummer, Christopher J. Sweeney, Shana Y. Trostel, Wilbert Zwart, Beatriz Germán, Xiaofeng A. Su, Scott Wilkinson, Henk G. van der Poel, Anson T. Ku, Andries M. Bergman, Adam G. Sowalsky, Elise M. Bekers, Sungyong You, Simon Linder, Jagpreet S. Nanda, Anis Hamid, Katherine L. Morel, Deborah L. Burkhart, Minhyung Kim, Leigh Ellis, Jina Kim, Ingrid Hofland, Duanduan Ma
article en
6 citations

Abstract

Phenotypic plasticity is a hallmark of cancer and is increasingly realized as a mechanism of resistance to androgen receptor-targeted (AR-targeted) therapy. Now that many prostate cancer (PCa) patients are treated upfront with AR-targeted agents, it is critical to identify actionable mechanisms that drive phenotypic plasticity, to prevent the emergence of resistance. We showed that loss of tristetraprolin (TTP; gene ZFP36) increased NF-κB activation, and was associated with higher rates of aggressive disease and early recurrence in primary PCa. We also examined the clinical and biological impact of ZFP36 loss with co-loss of PTEN, a known driver of PCa. Analysis of multiple independent primary PCa cohorts demonstrated that PTEN and ZFP36 co-loss was associated with increased recurrence risk. Engineering prostate-specific Zfp36 deletion in vivo induced prostatic intraepithelial neoplasia, and, with Pten codeletion, resulted in rapid progression to castration-resistant adenocarcinoma. Zfp36 loss altered the cell state driven by Pten loss, as demonstrated by enrichment of epithelial-mesenchymal transition (EMT), inflammation, TNF-α/NF-κB, and IL-6-JAK/STAT3 gene sets. Additionally, our work revealed that ZFP36 loss also induced enrichment of multiple gene sets involved in mononuclear cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor dimethylaminoparthenolide (DMAPT) induced marked therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed castration resistance.

Journal of Clinical InvestigationVol. 135(2)
Henry M. Jackson Foundation (US), Cedars-Sinai Medical Center (US), St. Jude Children's Research Hospital (US), Harvard University (US), Uniformed Services University of the Health Sciences (US), The University of Melbourne (AU), Dutch Cancer Society (NL), Walter Reed National Military Medical Center (US), The Netherlands Cancer Institute (NL), Oncode Institute (NL), Dana-Farber Cancer Institute (US), European Molecular Biology Laboratory (DE), Centre for Cancer Biology (AU), National Cancer Institute (US), Center for Cancer Research (US), The University of Adelaide (AU), Massachusetts Institute of Technology (US)
U.S. Department of Defense, Eli Lilly and Company, Pfizer, Sanofi, Harvard University, Exelixis, Astellas Pharma, Oncode Institute, Genentech, Uniformed Services University of the Health Sciences, National Cancer Institute
Zero hunger
Openalex Percentile: Top 10%
Prostate Cancer Treatment and Research
2.51
DOIOpen Access PDFOpenAlex
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