https://phaidra.vetmeduni.ac.at/o:2486 STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway Pencik, Jan Jan Pencik Medical University of Vienna / Center for Biomarker Research in Medicine / The Salk Institute for Biological Studies Kenner, Lukas Lukas Kenner 0000-0003-2184-1338 University of Veterinary Medicine Vienna / Medical University of Vienna Hacker, Marcus Marcus Hacker Medical University of Vienna Heery, David M. David M. Heery University of Nottingham Moazzami, Ali A. Ali A. Moazzami Swedish University of Agricultural Sciences Tang, Dean G. Dean G. Tang Roswell Park Comprehensive Cancer Center Speicher, Michael R. Michael R. Speicher Medical University of Graz Klocker, Helmut Helmut Klocker Medical University Innsbruck Kennedy, Richard D. Richard D. Kennedy Queen's University Belfast / Almac Diagnostics McKinney, Cathal Cathal McKinney Queen's University Belfast / Almac Diagnostics Carracedo, Arkaitz Arkaitz Carracedo Basque Research and Technology Alliance Moriggl, Richard Richard Moriggl 0000-0003-0918-9463 University of Veterinary Medicine Vienna Aberger, Fritz Fritz Aberger Paris-Lodron University of Salzburg Goffin, Vincent Vincent Goffin Université Paris Cité Hoermann, Gregor Gregor Hoermann Munich Leukemia Laboratory Armstrong, Chris W. D. Chris W. D. Armstrong Queen's University Belfast Jain, Suneil Suneil Jain Queen's University Belfast Poli, Valeria Valeria Poli University of Turin Rose-John, Stefan Stefan Rose-John University of Kiel Egger, Gerda Gerda Egger Medical University of Vienna / Ludwig Boltzmann Institute Applied Diagnostics Hantusch, Brigitte Brigitte Hantusch Medical University of Vienna Parkes, Eileen E. Eileen E. Parkes University of Oxford Turner, Suzanne D, Suzanne D, Turner University of Cambridge / Masaryk University Malcolm, Tim I. Tim I. Malcolm University of Cambridge Stoiber, Dagmar Dagmar Stoiber Medical University of Vienna / Karl Landsteiner University of Health Sciences Horvath, Jaqueline Jaqueline Horvath Medical University of Vienna Varady, Adam Adam Varady Medical University of Vienna Sternberg, Christina Christina Sternberg University of Veterinary Medicine Vienna / Medical University of Vienna / University of Kiel Pohl, Elena E. Elena E. Pohl 0000-0002-0604-5950 University of Veterinary Medicine Vienna Sternberg, Felix Felix Sternberg University of Veterinary Medicine Vienna Schäfer, Georg Georg Schäfer Medical University Innsbruck Hermanova, Ivana Ivana Hermanova Basque Research and Technology Alliance Tangermann, Simone Simone Tangermann University of Veterinary Medicine Vienna Östman, Johnny R. Johnny R. Östman Swedish University of Agricultural Sciences D'Andrea, David David D'Andrea Medical University of Vienna Greiner, Georg Georg Greiner Medical University of Vienna Redl, Elisa Elisa Redl Medical University of Vienna Dillinger, Thomas Thomas Dillinger Medical University of Vienna Witzeneder, Nadine Nadine Witzeneder Medical University of Vienna Orlova, Anna Anna Orlova 0000-0001-9262-7529 University of Veterinary Medicine Vienna Wingelhofer, Bettina Bettina Wingelhofer University of Veterinary Medicine Vienna Neubauer, Heidi A. Heidi A. Neubauer 0000-0001-7372-7786 University of Veterinary Medicine Vienna Aksoy, Osman Osman Aksoy Medical University of Vienna / Karl Landsteiner University of Health Sciences Heitzer, Ellen Ellen Heitzer Medical University of Graz Oberhuber, Monika Monika Oberhuber Center for Biomarker Research in Medicine Trachtová, Karolína Karolína Trachtová Medical University of Vienna / Masaryk University Lagger, Sabine Sabine Lagger 0000-0002-3032-9910 University of Veterinary Medicine Vienna Heidegger, Isabel Isabel Heidegger Medical University Innsbruck Tracz, Amanda Amanda Tracz Roswell Park Comprehensive Cancer Center Li, Wen Jess Wen Jess Li Roswell Park Comprehensive Cancer Center Grund-Gröschke, Sandra Sandra Grund-Gröschke Paris-Lodron University of Salzburg Pecoraro, Matteo Matteo Pecoraro Università Della Svizzera Italiana Atas, Emine Emine Atas Medical University of Vienna Schlederer, Michaela Michaela Schlederer Medical University of Vienna Philippe, Cecile Cecile Philippe Medical University of Vienna BMC text eng Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa. Transcription Factor; Signal Transducer; Gene-Expression; Cell-Growth; Metformin; Protein; Pten; Lkb1; Mtor; Identification http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:2486/download 10.1186/s12943-023-01825-8 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Molecular Cancer 22(1) (2023) Molecular Cancer 22 1 3.80 MB 2023