Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Sternberg, C; Raigel, M; Limberger, T; Trachtová, K; Schlederer, M; Lindner, D; Kodajova, P; Yang, J; Ziegler, R; Kalla, J; Stoiber, S; Dey, S; Zwolanek, D; Neubauer, HA; Oberhuber, M; Redmer, T; Hejret, V; Tichy, B; Tomberger, M; Harbusch, NS; Pencik, J; Tangermann, S; Bystry, V; Persson, JL; Egger, G; Pospisilova, S; Eferl, R; Wolf, P; Sternberg, F; Högler, S; Lagger, S; Rose-John, S; Kenner, L.
Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment.
Mol Cancer. 2024; 23(1):245
Doi: 10.1186/s12943-024-02114-8
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- Co-authors Med Uni Graz
- Dey Saptaswa
- Kenner Lukas
- Wolf Peter
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- Abstract:
- BACKGROUND: 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. 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: 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: 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Male - administration & dosage
- STAT3 Transcription Factor - metabolism
- Prostatic Neoplasms - pathology, metabolism, genetics
- Animals - administration & dosage
- Mice - administration & dosage
- Tumor Microenvironment - administration & dosage
- Humans - administration & dosage
- Tumor Suppressor Protein p53 - metabolism, genetics
- Cellular Senescence - administration & dosage
- Signal Transduction - administration & dosage
- Cell Line, Tumor - administration & dosage
- Gene Expression Regulation, Neoplastic - administration & dosage
- Cyclin-Dependent Kinase Inhibitor p16 - metabolism, genetics
- Disease Models, Animal - administration & dosage
- Find related publications in this database (Keywords)
- Prostate cancer
- IL6ST/STAT3 signaling
- L-gp130
- Senescence
- Senescence-associated secretory phenotype
- Tumor microenvironment
- Immune cell infiltration
- Cytotoxic T-cells