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Single cell analysis from prostates from PTEN(i)pe-/- and PTEN/VDR(i)pe-/-

ABSTRACT: Prostate cancer (PCa)-related deaths highly corelate with its metastatic spread due to limited efficiency of current therapies. In addition, the cases of de novo metastatic hormone-naïve prostate cancer (mHNPC) are increasing, highlighting the urgent need to identify novel biomarkers and treatment strategies for PCa spread. The impact of vitamin D receptor (VDR) signaling on prostate tumorigenesis remains unknown despite several epidemiologic studies suggesting its preventive role. Here, the consequences of VDR loss in prostatic epithelial cells (PECs) are studied using a relevant mouse model of PCa, Pten(i)pe−/− mice. We show that loss of VDR promotes oxidative stress in prostatic neoplasia that in turn enhances PECs proliferation. Moreover, VDR-loss leads to higher CXCL5 secretion by PTEN-deficient PECs, enhancing immunosuppressive neutrophils infiltration in prostates. Additionally, our data highlight elevated circulating neutrophil levels as a biomarker for PTEN-deficient PCa dissemination to the liver, and show the efficiency of targeting neutrophil chemotaxis to limit cancer spread. Overall, this work demonstrates how vitamin D signaling slows down PTEN-loss driven tumorigenesis and suggests new therapeutic and diagnostic strategies for mHNPC.

ORGANISM(S): Mus musculus

PROVIDER: GSE281153 | GEO | 2026/01/12

REPOSITORIES: GEO

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Project description:Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related mortility among men in western societies. PCa exhibits a protracted progression, initiating as Prostatic Intraepithelial Neoplasia (PIN), advancing to adenocarcinoma, and eventually culminating in metastatic dissemination. The advent of Immune Checkpoint Inhibitors (ICI) has been revolutionized the field of cancer immunology. However, the efficacy of immunotherapy in PCa has been limited, and the role of immune cells in prostate tumorigenesis has only recently been explored. In this study, we performed an in-depth characterization of immune cells in healthy murine prostate and during PCa progression in PTEN(i)pe-/- mice. In this model, the PTEN gene is selectively ablated in prostatic luminal epithelial cells at adulthood (PSA-CreERT2), closely mimicking human PCa development. Notably, tumor progression in this model is gradual, with the PIN stage manifesting at 3 months post-gene invalidation and the adenocarcinoma stage at 9 months. The strict temporal control of PTEN depletion coupled with the slow tumor progression, makes the PTEN(i)pe-/- mouse model an invaluable tool for delineating immune infiltration during tumor development and evaluating therapeutic interventions. Here we performed scRNAseq on CD45+ immune cells residing in the dorsolateral lobes of prostate at respectively 3 and 9 months post tamoxifen treatment of PTEN(i)pe-/- and control mice, allowing to establish a high-resolution immune atlas of murine PCa from neoplasia to adenocarcinoma. Our findings reveal significant heterogeneity among mononuclear phagocytes (dendritic cells and macrophages), neutrophils and lymphoid immune cells in the prostate. Various neutrophil clusters exhibit an immunosuppressive signature from the PIN stage onward. We observed the recruitment of Trem2+ tumor-associated macrophage subset during PCa, potentially contributing to tumorigenesis. Additionally, there was an increase in CD8+ T lymphocytes in PCa, which exhibited an activated/exhausted phenotype. Our study elucidates the intricate dynamics of immune cell behavior in PCa from early to late stages. These insights pave the way for novel immunotherapeutic strategies to treat prostate cancer, thereby advancing the field of tumor immunology.

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Single cell analysis from prostates from PTEN(i)pe-/- and PTEN/VDR(i)pe-/-

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