o:2486 STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway en 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 1552099 10.1186/s12943-023-01825-8 2024-02-05T09:55:28.612Z 44 yes 46 Jan Pencik Medical University of Vienna / Center for Biomarker Research in Medicine / The Salk Institute for Biological Studies Lukas Kenner University of Veterinary Medicine Vienna / Medical University of Vienna person 0000-0003-2184-1338 Marcus Hacker Medical University of Vienna person David M. Heery University of Nottingham person Ali A. Moazzami Swedish University of Agricultural Sciences person Dean G. Tang Roswell Park Comprehensive Cancer Center person Michael R. Speicher Medical University of Graz person Helmut Klocker Medical University Innsbruck person Richard D. Kennedy Queen's University Belfast / Almac Diagnostics person Cathal McKinney Queen's University Belfast / Almac Diagnostics person Arkaitz Carracedo Basque Research and Technology Alliance person Richard Moriggl University of Veterinary Medicine Vienna person 0000-0003-0918-9463 Fritz Aberger Paris-Lodron University of Salzburg person Vincent Goffin Université Paris Cité person Gregor Hoermann Munich Leukemia Laboratory person Chris W. D. Armstrong Queen's University Belfast person Suneil Jain Queen's University Belfast person Valeria Poli University of Turin person Stefan Rose-John University of Kiel person Gerda Egger Medical University of Vienna / Ludwig Boltzmann Institute Applied Diagnostics person Brigitte Hantusch Medical University of Vienna person Eileen E. Parkes University of Oxford person Suzanne D, Turner University of Cambridge / Masaryk University person Tim I. Malcolm University of Cambridge person Dagmar Stoiber Medical University of Vienna / Karl Landsteiner University of Health Sciences person Jaqueline Horvath Medical University of Vienna person Adam Varady Medical University of Vienna person Christina Sternberg University of Veterinary Medicine Vienna / Medical University of Vienna / University of Kiel person Elena E. Pohl University of Veterinary Medicine Vienna person 0000-0002-0604-5950 Felix Sternberg University of Veterinary Medicine Vienna person Georg Schäfer Medical University Innsbruck person Ivana Hermanova Basque Research and Technology Alliance person Simone Tangermann University of Veterinary Medicine Vienna person Johnny R. Östman Swedish University of Agricultural Sciences person David D'Andrea Medical University of Vienna person Georg Greiner Medical University of Vienna person Elisa Redl Medical University of Vienna person Thomas Dillinger Medical University of Vienna person Nadine Witzeneder Medical University of Vienna person Anna Orlova University of Veterinary Medicine Vienna person 0000-0001-9262-7529 Bettina Wingelhofer University of Veterinary Medicine Vienna person Heidi A. Neubauer University of Veterinary Medicine Vienna person 0000-0001-7372-7786 Osman Aksoy Medical University of Vienna / Karl Landsteiner University of Health Sciences person Ellen Heitzer Medical University of Graz person Monika Oberhuber Center for Biomarker Research in Medicine person Karolína Trachtová Medical University of Vienna / Masaryk University person Sabine Lagger University of Veterinary Medicine Vienna person 0000-0002-3032-9910 Isabel Heidegger Medical University Innsbruck person Amanda Tracz Roswell Park Comprehensive Cancer Center person Wen Jess Li Roswell Park Comprehensive Cancer Center person Sandra Grund-Gröschke Paris-Lodron University of Salzburg person Matteo Pecoraro Università Della Svizzera Italiana person Emine Atas Medical University of Vienna person Michaela Schlederer Medical University of Vienna person Cecile Philippe Medical University of Vienna person application/pdf 3986680 https://phaidra.vetmeduni.ac.at/o:2486 no yes 16 70 1552253 Molecular Cancer 25 22 1 BMC 2023