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

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

doi:10.1186/s12943-024-02114-8

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Title (eng)

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

Author

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

Abstract (eng)

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.

Keywords (eng)

Prostate CancerIL6ST/STAT3 SignalingL-gp130SenescenceSenescence-associated Secretory PhenotypeTumor MicroenvironmentImmune Cell InfiltrationCytotoxic T-Cells

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:3743

DOI

10.1186/s12943-024-02114-8

Is in series

Title (eng)

Molecular Cancer

Volume