University of Veterinary Medicine Vienna JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression 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.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.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? production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1? 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?, TNF-?, 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.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. en TEXT article Male; Prostatic Neoplasmspathologygeneticsmetabolism; Animals; Mice; Humans; PTEN Phosphohydrolasegeneticsmetabolism; Disease Progression; Tumor Microenvironmentimmunology; Senescence-Associated Secretory Phenotype; Proto-Oncogene Proteins c-junmetabolism; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Gene Expression Profiling; Cellular Senescencegenetics; Disease Models, Animal 2024 2024 Redmer, Torben (University of Veterinary Medicine Vienna) Kenner, Lukas (University of Veterinary Medicine Vienna / Medical University of Vienna / CBmed GmbH) Bystry, Vojtech (Masaryk University) Tichy, Boris (Masaryk University) Theurillat, Jean-Philippe Moriggl, Richard (Paris-Lodron University of Salzburg) Garces de Los Fayos Alonso, Ines (University of Veterinary Medicine Vienna / Medical University of Vienna) Harbusch, Nora S. (CBmed GmbH) Tomberger, Martina (CBmed GmbH) Miranda, Sara (University of Veterinary Medicine Vienna) Neubauer, Heidi A. (University of Veterinary Medicine Vienna) Bolis, Marco Lagger, Sabine (University of Veterinary Medicine Vienna) Oberhuber, Monika (CBmed GmbH) Stoiber , Stefan (Medical University Vienna) Schlederer, Michaela (Medical University of Vienna) Högler, Sandra (University of Veterinary Medicine Vienna) Kodajova, Petra (University of Veterinary Medicine Vienna) Trachtova, Karolina (Medical University of Vienna / Masaryk University) Limberger, Tanja (Medical University of Vienna) Aufinger, Astrid (Medical University Vienna) Lindner, Desiree (University of Veterinary Medicine Vienna / Medical University of Vienna) Probst, Clara (University of Veterinary Medicine Vienna / Medical University of Vienna) Egger, Gerda (Medical University of Vienna) Ziegler, Roman (University of Veterinary Medicine Vienna / Charles University) Raigel, Martin (University of Veterinary Medicine Vienna / Medical University of Vienna) Sternberg, Christina (University of Veterinary Medicine Vienna / Medical University of Vienna / University of Kiel) Merkel, Olaf (Medical University of Vienna) Pospisilova, Sarka (Masaryk University) Strobl, Birgit (University of Veterinary Medicine Vienna) Aberger, Fritz (Paris-Lodron University of Salzburg) Mathas, Stephan Persson, Jenny L (Umeå University / Malmö Universitet) BMC