Study of vitamin D signaling pathways during the initiation of prostate cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE281118 | GEO | 2026/01/12
REPOSITORIES: GEO
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Project description: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.
2026-01-12 | GSE281153 | GEO
Project description:Epidemiological data have linked vitamin D deficiency to the onset of various cancers, including prostate cancer, and although in-vitro studies have demonstrated anti-cancer activities for the vitamin, clinical trials provided conflicting results. To determine the impact of vitamin D signaling on prostatic precancerous lesions, we treated genetically-engineered mice harboring prostatic intraepithelial neoplasia (PIN) with Gemini-72, a vitamin D analogue with reported anti-cancer activities, and comprehensively analyzed its effects on various cell types in such lesions. We show that this analogue induces apoptosis in senescent PINs and normalizes extracellular matrix remodeling by stromal fibroblasts in an epithelial VDR-dependent manner. Furthermore, it reduces the prostatic infiltration of immunosuppressive myeloid-derived suppressor cells in an epithelial VDR-independent manner. Moreover, single-cell RNA-sequencing analysis demonstrates that while a subset of luminal epithelial cells, expressing Krt4 and Tacstd2 (termed luminal-C) with enhanced interferon signature, is lost by such a treatment, anti-apoptotic pathways are induced in persistent luminal-C cells. Therefore, our findings delineate the distinct responses of prostatic precancerous lesions and the microenvironment to the vitamin D analogue, and shed light on mechanisms that limit treatment’s efficacy.
2021-08-04 | GSE164856 | GEO
Project description:Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of prostatic precancerous lesions to malignant tumors provides a broad time-frame for strategies targeting disease emergence. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on prostates of genetically-engineered Pten(i)pe- /- mice. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells during disease progression. Luminal HIF1A enhances glucose metabolism and promotes a PIN-derived secretome that increases the recruitment of myeloid-derived suppressor cells, thus dampening immune surveillance. Moreover, pharmacological inhibition of HIF1A induces apoptosis in early PIN lesions, and slows the proliferation of late ones. Therefore, our study identifies HIF1A as a target for PCa prevention. Importantly, we also demonstrate that HIF1A signaling correlates with the emergence of prostatic luminal cells expressing TGM2, the expression of which predicts early relapse after primary intervention in PCa patients.
2022-06-07 | GSE186419 | GEO
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.
2025-09-30 | GSE271451 | GEO
Project description:Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of precancerous lesions to malignant tumors provides a broad time-frame for preventing PCa. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on Pten(i)pe-/- mice which recapitulate prostate carcinogenesis in humans. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells, which enhances malignant progression. Luminal HIF1A dampens immune surveillance and drives luminal plasticity leading to the emergence of cells with selective Transglutaminase 2 (TGM2) expression and impaired androgen signaling. Importantly, elevated TGM2 levels in PCa patients are associated with shortened progression-free survival after prostatectomy. Finally, we show that pharmacologically inhibiting HIF1A impairs cell proliferation and induces apoptosis in PINs. Therefore, our study demonstrates that HIF1A is a target for PCa prevention, and that TGM2 is a promising prognostic biomarker of early relapse after prostatectomy.
2022-06-07 | GSE189784 | GEO
Project description:We treated PTENpe-/- mice, in which PTEN is selectively ablated in prostatic epithelial cells, with a Vitamin D analog. We extracted RNA from the prostate of oil (vehicle) and Vitamin D analog-treated mice.
2021-08-04 | GSE164855 | GEO
Project description:ChIP with VDR antibody followed by DNA sequencing to determine if VDR binds the LMNA gene locus
2017-01-13 | GSE76884 | GEO
Project description:Prostate epithelium develops from multipotent stem cells (SCs) which are replaced in adult life by different lineage-restricted basal and luminal unipotent SCs that sustain the homeostasis in a regionalized manner. Deletion of Pten re-induces multipotency in basal cells (BC). However, the molecular mechanisms regulating cell plasticity and tumor initiation are poorly understood. Here, we showed that Pten deletion in BCs led to distinct cell fate reprograming and tumor initiation in a regionalized manner. In anterior and dorsal prostates, BCs were reprogrammed into a Hillock like state that progressed into a basal-luminal hybrid state, which further transitioned into a proximal-like luminal state before progressing to tumorigenesis. In the ventral prostate, BC expressing Nkx3.1 gave rise to distal-like luminal state that are less plastic and progress more slowly to tumorigenesis. Single-cell sequencing and ATAC-seq analysis showed that the reprograming into hillock and proximal states induced activation of the innate immunity pathway during the cellular reprograming and tumor formation. Targeting Il-1, JAK/STAT and Nfkb inhibits Pten-induced cell plasticity and oncogenic reprograming, opening new opportunities in the prevention and treatment of prostate cancer.
2025-04-24 | GSE270187 | GEO
Project description:Prostate epithelium develops from multipotent stem cells (SCs) which are replaced in adult life by different lineage-restricted basal and luminal unipotent SCs that sustain the homeostasis in a regionalized manner. Deletion of Pten re-induces multipotency in basal cells (BC). However, the molecular mechanisms regulating cell plasticity and tumor initiation are poorly understood. Here, we showed that Pten deletion in BCs led to distinct cell fate reprograming and tumor initiation in a regionalized manner. In anterior and dorsal prostates, BCs were reprogrammed into a Hillock like state that progressed into a basal-luminal hybrid state, which further transitioned into a proximal-like luminal state before progressing to tumorigenesis. In the ventral prostate, BC expressing Nkx3.1 gave rise to distal-like luminal state that are less plastic and progress more slowly to tumorigenesis. Single-cell sequencing and ATAC-seq analysis showed that the reprograming into hillock and proximal states induced activation of the innate immunity pathway during the cellular reprograming and tumor formation. Targeting Il-1, JAK/STAT and Nfkb inhibits Pten-induced cell plasticity and oncogenic reprograming, opening new opportunities in the prevention and treatment of prostate cancer.
2025-04-24 | GSE270191 | GEO
Project description:Prostate epithelium develops from multipotent stem cells (SCs) which are replaced in adult life by different lineage-restricted basal and luminal unipotent SCs that sustain the homeostasis in a regionalized manner. Deletion of Pten re-induces multipotency in basal cells (BC). However, the molecular mechanisms regulating cell plasticity and tumor initiation are poorly understood. Here, we showed that Pten deletion in BCs led to distinct cell fate reprograming and tumor initiation in a regionalized manner. In anterior and dorsal prostates, BCs were reprogrammed into a Hillock like state that progressed into a basal-luminal hybrid state, which further transitioned into a proximal-like luminal state before progressing to tumorigenesis. In the ventral prostate, BC expressing Nkx3.1 gave rise to distal-like luminal state that are less plastic and progress more slowly to tumorigenesis. Single-cell sequencing and ATAC-seq analysis showed that the reprograming into hillock and proximal states induced activation of the innate immunity pathway during the cellular reprograming and tumor formation. Targeting Il-1, JAK/STAT and Nfkb inhibits Pten-induced cell plasticity and oncogenic reprograming, opening new opportunities in the prevention and treatment of prostate cancer.
2025-04-24 | GSE270190 | GEO