Molecular Cancer 22(1) (2023) 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. BMC STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway CC BY 4.0 International http://creativecommons.org/licenses/by/4.0/ application/pdf doi:10.1186/s12943-023-01825-8 https://phaidra.vetmeduni.ac.at/o:2486 eng 2023 Transcription Factor; Signal Transducer; Gene-Expression; Cell-Growth; Metformin; Protein; Pten; Lkb1; Mtor; Identification Pencik, Jan (Medical University of Vienna / Center for Biomarker Research in Medicine / The Salk Institute for Biological Studies) Kenner, Lukas (University of Veterinary Medicine Vienna / Medical University of Vienna) Carracedo, Arkaitz (Basque Research and Technology Alliance) Moriggl, Richard (University of Veterinary Medicine Vienna) Aberger, Fritz (Paris-Lodron University of Salzburg) Goffin, Vincent (Université Paris Cité) Hoermann, Gregor (Munich Leukemia Laboratory) Armstrong, Chris W. D. (Queen's University Belfast) Jain, Suneil (Queen's University Belfast) Poli, Valeria (University of Turin) Rose-John, Stefan (University of Kiel) Egger, Gerda (Medical University of Vienna / Ludwig Boltzmann Institute Applied Diagnostics) Hacker, Marcus (Medical University of Vienna) Hantusch, Brigitte (Medical University of Vienna) Parkes, Eileen E. (University of Oxford) Turner, Suzanne D, (University of Cambridge / Masaryk University) Malcolm, Tim I. (University of Cambridge) Stoiber, Dagmar (Medical University of Vienna / Karl Landsteiner University of Health Sciences) Horvath, Jaqueline (Medical University of Vienna) Varady, Adam (Medical University of Vienna) Sternberg, Christina (University of Veterinary Medicine Vienna / Medical University of Vienna / University of Kiel ) Pohl, Elena E. (University of Veterinary Medicine Vienna) Sternberg, Felix (University of Veterinary Medicine Vienna) Heery, David M. (University of Nottingham) Schäfer, Georg (Medical University Innsbruck) Hermanova, Ivana (Basque Research and Technology Alliance) Tangermann, Simone (University of Veterinary Medicine Vienna) Östman, Johnny R. (Swedish University of Agricultural Sciences) D'Andrea, David (Medical University of Vienna) Greiner, Georg (Medical University of Vienna) Redl, Elisa (Medical University of Vienna) Dillinger, Thomas (Medical University of Vienna) Witzeneder, Nadine (Medical University of Vienna) Orlova, Anna (University of Veterinary Medicine Vienna) Moazzami, Ali A. (Swedish University of Agricultural Sciences) Wingelhofer, Bettina (University of Veterinary Medicine Vienna) Neubauer, Heidi A. (University of Veterinary Medicine Vienna) Aksoy, Osman (Medical University of Vienna / Karl Landsteiner University of Health Sciences) Heitzer, Ellen (Medical University of Graz) Oberhuber, Monika (Center for Biomarker Research in Medicine) Trachtová, Karolína (Medical University of Vienna / Masaryk University) Lagger, Sabine (University of Veterinary Medicine Vienna) Heidegger, Isabel (Medical University Innsbruck) Tracz, Amanda (Roswell Park Comprehensive Cancer Center) Li, Wen Jess (Roswell Park Comprehensive Cancer Center) Tang, Dean G. (Roswell Park Comprehensive Cancer Center) Grund-Gröschke, Sandra (Paris-Lodron University of Salzburg) Pecoraro, Matteo (Università Della Svizzera Italiana) Atas, Emine (Medical University of Vienna) Schlederer, Michaela (Medical University of Vienna) Philippe, Cecile (Medical University of Vienna) Speicher, Michael R. (Medical University of Graz) Klocker, Helmut (Medical University Innsbruck) Kennedy, Richard D. (Queen's University Belfast / Almac Diagnostics) McKinney, Cathal (Queen's University Belfast / Almac Diagnostics) article