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.
Molecular cancer. 2024 Oct 31*** epublish ***
Christina Sternberg, Martin Raigel, Tanja Limberger, Karolína Trachtová, Michaela Schlederer, Desiree Lindner, Petra Kodajova, Jiaye Yang, Roman Ziegler, Jessica Kalla, Stefan Stoiber, Saptaswa Dey, Daniela Zwolanek, Heidi A Neubauer, Monika Oberhuber, Torben Redmer, Václav Hejret, Boris Tichy, Martina Tomberger, Nora S Harbusch, Jan Pencik, Simone Tangermann, Vojtech Bystry, Jenny L Persson, Gerda Egger, Sarka Pospisilova, Robert Eferl, Peter Wolf, Felix Sternberg, Sandra Högler, Sabine Lagger, Stefan Rose-John, Lukas Kenner
Department of Pathology, Medical University of Vienna, Vienna, Austria. ., Department of Pathology, Medical University of Vienna, Vienna, Austria., Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria., Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria., Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria., Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center, Vienna, Austria., Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria., Center for Biomarker Research in Medicine GmbH (CBmed), Graz, Styria, Austria., Central European Institute of Technology, Masaryk University, Brno, Czech Republic., Department of Molecular Biology, Umeå University, Umeå, Sweden., Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, Vienna, Austria., Biochemical Institute, University of Kiel, Kiel, Germany. ., Department of Pathology, Medical University of Vienna, Vienna, Austria. .