Abstract 5283: Decoding and disrupting the coupled cellular plasticity and myeloid cell instigation in metastatic prostate cancer

Abstract Prostate cancer (PCa) metastasis significantly worsens patient prognosis, particularly when it spreads to the lungs. Understanding the mechanisms underlying PCa metastasis is crucial for developing effective therapies. Here, we developed a genetically engineered mouse model by activating MAPK pathway in the PB-Cre Pten p53 Smad4 mice, creating a model that mimics the aberrant cell signaling associated with human metastatic PCa and exhibits strong metastatic phenotype. We observed dynamic changes in epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) during metastasis: circulating tumor cells (CTCs) displayed mesenchymal characteristics, while lung metastases regained epithelial features. Transcriptomic profiling of primary tumors, CTCs, and lung metastases revealed that lung metastatic cells (LM) upregulated pro-inflammatory cytokines, notably IL-1α. This cytokine profile correlated with increased recruitment and activation of neutrophils in the premetastatic lung niche, as confirmed by single-cell RNA sequencing and flow cytometry. Functional experiments demonstrated that depleting neutrophils using anti-Ly6G antibodies or inhibiting their recruitment and activation via a CXCR1/2 antagonist (currently in clinical trials) significantly reduced lung metastasis and extended survival in mice. Similarly, IL-1 receptor knockout mice showed decreased neutrophil infiltration and fewer metastatic nodules, indicating the pivotal role of IL-1 signaling in neutrophil-mediated metastasis. Mechanistically, we identified the transcription factor KLF4 as the master regulator of both the EMT-to-MET plasticity and IL-1α expression in metastatic cells. Chromatin immunoprecipitation confirmed KLF4 binding to the IL-1α promoter, leading to the upregulation of neutrophil-recruiting cytokines. Knockdown of KLF4 in LM cells reduced IL-1α levels and metastasis, while overexpression enhanced them. Co-culture of tumor cells with neutrophils increased KLF4 expression and cytokine production, suggesting a feedback loop promoting metastasis. Clinical data analysis showed that high levels of KLF4 and IL-1α correlate with increased neutrophil infiltration and poorer disease-free survival in PCa patients. Our findings identify the crucial role of the KLF4/IL-1α axis and neutrophil recruitment in PCa lung metastasis. Targeting neutrophil activation or the KLF4/IL-1α signaling pathway may offer new therapeutic strategies for preventing or treating metastatic prostate cancer. Citation Format: Tianhe Huang, Yaoyin Li, Jun Wan, Liang Cheng, Xin Lu. Decoding and disrupting the coupled cellular plasticity and myeloid cell instigation in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5283.