Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment.

Male STAT3 Transcription Factor / metabolism Prostatic Neoplasms / pathology Animals Mice Tumor Microenvironment Humans Tumor Suppressor Protein p53 / metabolism Cellular Senescence Signal Transduction Cell Line, Tumor Gene Expression Regulation, Neoplastic Cyclin-Dependent Kinase Inhibitor p16 / metabolism Disease Models, Animal

Cytotoxic T-cells IL6ST/STAT3 signaling Immune cell infiltration L-gp130 Prostate cancer Senescence Senescence-associated secretory phenotype Tumor microenvironment

Journal

Molecular cancer

ISSN: 1476-4598

Titre abrégé: Mol Cancer

Pays: England

ID NLM: 101147698

Informations de publication

Date de publication:
31 Oct 2024

Historique:

received: 17 03 2024

accepted: 05 09 2024

medline: 1 11 2024

pubmed: 1 11 2024

entrez: 1 11 2024

Statut: epublish

Résumé

Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood. To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses. Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.

Sections du résumé

BACKGROUND BACKGROUND

METHODS METHODS

To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses.

RESULTS RESULTS

Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor.

CONCLUSIONS CONCLUSIONS

Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.

Identifiants

DOI: 10.1186/s12943-024-02114-8 PMID: 39482716

pubmed: 39482716

doi: 10.1186/s12943-024-02114-8

pii: 10.1186/s12943-024-02114-8

doi:

Substances chimiques

STAT3 Transcription Factor 0

Tumor Suppressor Protein p53 0

Cyclin-Dependent Kinase Inhibitor p16 0

STAT3 protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

245

Informations de copyright

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