JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression

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Authors	REDMER Torben RAIGEL Martin STERNBERG Christina ZIEGLER Roman PROBST Clara LINDNER Desiree AUFINGER Astrid LIMBERGER Tanja TRACHTOVÁ Karolína KODAJOVA Petra HOEGLER Sandra SCHLEDERER Michaela STOIBER Stefan OBERHUBER Monika BOLIS Marco NEUBAUER Heidi A MIRANDA Sara TOMBERGER Martina HARBUSCH Nora S INES Garces de los Fayos Alonso STERNBERG Felix MORIGGL Richard THEURILLAT Jean-Philippe TICHÝ Boris BYSTRÝ Vojtěch PERSSON Jenny L MATHAS Stephan ABERGER Fritz STROBL Birgit POSPÍŠILOVÁ Šárka MERKEL Olaf EGGER Gerda LAGGER Sabine KENNER Lukas
Year of publication	2024
Type	Article in Periodical
Magazine / Source	Molecular Cancer
MU Faculty or unit	Central European Institute of Technology
Citation
Web	https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02022-x
Doi	http://dx.doi.org/10.1186/s12943-024-02022-x
Keywords	Prostate cancer; AP-1 transcription factors; JUN; Senescence; SASP; Immune infiltration
Attached files	JUN_mediates_the_senescence_associated_secretory_phenotype_and_immune_cell_recruitment_to_prevent_prostate_cancer_progression.pdf
Description	Background Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood.Methods We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment.Results Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1 beta production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1 beta and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1 beta, TNF-alpha, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth.Conclusions Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.
Related projects:	National institute for cancer research NCMG: The National Centre for Medical Genomic