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Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice
Katherine L. Morel, … , Christopher J. Sweeney, Leigh Ellis
Katherine L. Morel, … , Christopher J. Sweeney, Leigh Ellis
Published November 19, 2024
Citation Information: J Clin Invest. 2025;135(2):e175680. https://doi.org/10.1172/JCI175680.
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Research Article Cell biology Oncology Article has an altmetric score of 25

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

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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.

Authors

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

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Figure 7

Zfp36 loss drives castration resistance in Pten-null murine tumors, which is counteracted with the NF-κB inhibitor DMAPT.

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Zfp36 loss drives castration resistance in Pten-null murine tumors, whi...
(A) Kaplan-Meier graph aged GEMMs (Mantel-Cox log-rank test). Whole prostate weights 12 weeks after castration. n = 5 mice per genotype, *P < 0.05, ***P < 0.0005 (1-way ANOVA with Tukey’s post hoc). (B) GEMM-derived organoid growth with and without enzalutamide (10 μM). n = 1 unique organoid line per genotype, repeated twice; experiments are denoted by unique symbols; *P < 0.05, ***P < 0.0005 (2-tailed multiple t test). (C) Allograft tumor growth in mice treated with DMAPT (100 mg/kg/d) or vehicle with or without surgical castration. n = 5 mice per treatment group. (D) Allograft endpoint tumor volumes. n = 5 mice per treatment group, *P < 0.05, **P < 0.005, ****P < 0.0001 (1-way ANOVA with Tukey’s post hoc). (E and F) Representative images (E) and quantification (F) of cell death (green) in GEMM-derived PCa organoids treated with DMAPT (5 μM), enzalutamide (10 μM), or the combination of both for 72 hours. n = 5 unique organoid lines per genotype, repeated once; experiments 1 and 2 are denoted by unique symbols (technical replicates are underlaid in gray); ****P < 0.0001 (1-way ANOVA with Tukey’s post hoc). Scale bars: 100 μm. (G) Flow cytometry quantification for CD45, synaptophysin, and AR expression in GEMM-derived PCa organoids treated with DMAPT (5 μM) or DMSO vehicle for 72 hours. n = 3 per genotype. *P < 0.05; **P < 0.005; ***P < 0.0005 (2-way ANOVA with Fisher’s least significant difference (LSD) test). (H) Fold change of Fkbp5 in GEMM-derived 2D cell lines treated with DMAPT (5 μM) or DMSO vehicle for 72 hours with or without R1881 (10 nM) stimulation. n = 1 organoid line per genotype, repeated twice; experiments 1, 2, and 3 are denoted by unique symbols; *P < 0.05, **P < 0.005, ***P < 0.0005, ****P < 0.0001 (1-way ANOVA with Tukey’s post hoc). (I) Schematic overview with ZFP36 intact, epithelial cells present with a luminal lineage phenotype and sensitivity to AR inhibition. In response to increased NF-κB expression, ZFP36/TTP increases as part of a negative-feedback loop. Loss of ZFP36 results in an alternative epithelial cell lineage phenotype, with uncontrolled NF-κB activation and reduced response to AR inhibition. DMAPT treatment restores a more luminal epithelial cell type and sensitivity to AR inhibition.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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