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

C. Sternberg, M. Raigel, T. Limberger, K. Trachtová, M. Schlederer, D. Lindner, P. Kodajova, J. Yang, R. Ziegler, J. Kalla, S. Stoiber, S. Dey, D. Zwolanek, HA. Neubauer, M. Oberhuber, T. Redmer, V. Hejret, B. Tichy, M. Tomberger, NS. Harbusch,...

. 2024 ; 23 (1) : 245. [pub] 20241031

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25003758

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.

Biochemical Institute University of Kiel Kiel Germany

BioTechMed Graz Graz Austria

Center for Biomarker Research in Medicine GmbH Graz Styria Austria

Center for Cancer Research Medical University of Vienna and Comprehensive Cancer Center Vienna Austria

Central European Institute of Technology Masaryk University Brno Czech Republic

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna Vienna Austria

Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Biological Sciences and Pathobiology Physiology and Biophysics University of Veterinary Medicine Vienna Vienna Austria

Department of Biomedical Imaging and Image Guided Therapy Division of Nuclear Medicine Medical University of Vienna Vienna Austria

Department of Biomedical Sciences Malmö Universitet Malmö Sweden

Department of Cell Biology Charles University Prague Czech Republic and Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University Vestec u Prahy Czech Republic

Department of Dermatology and Venereology Medical University of Graz Graz Austria

Department of Molecular Biology Umeå University Umeå Sweden

Department of Nutritional Sciences Faculty of Life Sciences University of Vienna Vienna Austria

Department of Pathology Medical University of Vienna Vienna Austria

Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna Vienna Austria

Institute of Medical Biochemistry University of Veterinary Medicine Vienna Vienna Austria

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna Austria

Citace poskytuje Crossref.org

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$a Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment / $c C. Sternberg, M. Raigel, T. Limberger, K. Trachtová, M. Schlederer, D. Lindner, P. Kodajova, J. Yang, R. Ziegler, J. Kalla, S. Stoiber, S. Dey, D. Zwolanek, HA. Neubauer, M. Oberhuber, T. Redmer, V. Hejret, B. Tichy, M. Tomberger, NS. Harbusch, J. Pencik, S. Tangermann, V. Bystry, JL. Persson, G. Egger, S. Pospisilova, R. Eferl, P. Wolf, F. Sternberg, S. Högler, S. Lagger, S. Rose-John, L. Kenner
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$a 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.
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