Publication details

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

Authors	STERNBERG Christina RAIGEL Martin LIMBERGER Tanja TRACHTOVÁ Karolína SCHLEDERER Michaela LINDNER Desiree KODAJOVA Petra YANG Jiaye ZIEGLER Roman KALLA Jessica STOIBER Stefan DEY Saptaswa ZWOLANEK Daniela NEUBAUER Heidi A OBERHUBER Monika REDMER Torben HEJRET Václav TICHÝ Boris TOMBERGER Martina HARBUSCH Nora S PENCIK Jan TANGERMANN Simone BYSTRÝ Vojtěch PERSSON Jenny L EGGER Gerda POSPÍŠILOVÁ Šárka EFERL Robert WOLF Peter STERNBERG Felix HOGLER Sandra LAGGER Sabine ROSE-JOHN Stefan KENNER Lukas
Year of publication	2024
Type	Article in Periodical
Magazine / Source	Molecular Cancer
MU Faculty or unit	Faculty of Medicine
Citation
web	https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02114-8
Doi	http://dx.doi.org/10.1186/s12943-024-02114-8
Keywords	Prostate cancer; IL6ST/STAT3 signaling; L-gp130; Senescence; Senescence-associated secretory phenotype; Tumor microenvironment; Immune cell infiltration; Cytotoxic T-cells
Attached files	Cell-autonomous_IL6ST_activation_suppresses_prostate_cancer_development_via_STAT3_ARF_p53-driven_senescence_and_confers_an_immune-active_tumor_microenvironment.pdf
Description	BackgroundProstate 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.MethodsTo 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.ResultsGenetic 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.ConclusionsOur 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.
Related projects:	National institute for cancer research