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

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

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 5

Increased metastatic potential occurs with Zfp36 loss in Pten-null murine tumors.

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Increased metastatic potential occurs with Zfp36 loss in Pten-null murin...
(A) GSEA from RNA-Seq of endpoint GEMM PCa tumors comparing Pten–/– and Pten–/– Zfp36–/– GEMMs, highlighting significant positively and negatively enriched GOBP pathways. (B) Ki-67 IHC and Krt18 and αSMA IF staining PCa in Pten–/–, Pten–/– Zfp36+/–, and Pten–/– Zfp36–/– GEMM dorsolateral prostate tissue at 38 weeks, with corresponding quantification. Increased tumor cell proliferation and basement membrane breakdown are observed with loss of Zfp36. n = 5 mice per genotype, *P < 0.05, **P < 0.005, ***P < 0.0005 (1-way ANOVA with Tukey’s post hoc). Scale bar: 100 μm. (C) Number of mice that displayed PCa cells in distant organs by recombination PCR in Pten–/–, Pten–/– Zfp36+/–, and Pten–/– Zfp36–/– GEMMs. (D) Representative images and quantification of the full scan in FFPE sections of tumor-adjacent pelvic lymph nodes (LNs) in Pten–/– and Pten–/– Zfp36–/– mice. LNs were stained by multiplex IHC for Epcam (green), AR (red), and synaptophysin (Syp; white). Positive cells identify epithelial/tumoral cells metastasizing LNs (n = 3 mice per genotype). Scale bar: 50 μm. (E) Representative images and quantification of budding in GEMM-derived organoids highlighting increased invasive and metastatic potential of Pten–/– Zfp36–/– organoids. n = 5 unique organoid lines per genotype with experiment repeated once; experiments 1 and 2 are denoted by different symbols (technical replicates are underlaid in gray); ****P < 0.0001 (2-tailed Student’s t test). (F) Scratch assay in GEMM-derived 2D cells, comparing Pten–/– and Pten–/– Zfp36–/– wound healing with that of Pten–/– Rb1–/–, a previously described metastatic, neuroendocrine PCa murine cell line (32). Representative images of scratch assay have been overlaid with areas identified as wound infiltrate in black. n = 1 cell line per genotype with experiment repeated twice; experiments 1, 2, and 3 are denoted by unique symbols; *P < 0.05, ***P < 0.001, ****P < 0.0001 (2-way ANOVA with Tukey’s post hoc).