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.

Almac Diagnostics Craigavon BT63 5QD UK

Biochemical Institute University of Kiel 24098 Kiel Germany

Center for Biomarker Research in Medicine 8010 Graz Austria

Center for Cooperative Research in Biosciences Basque Research and Technology Alliance 20850 Derio Spain

Central European Institute of Technology Masaryk University 60177 Brno Czech Republic

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna 1090 Vienna Austria

Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria

Department for Basic and Translational Oncology and Hematology Division Molecular Oncology and Hematology Karl Landsteiner University of Health Sciences 3500 Krems Austria

Department of Biosciences and Medical Biology Cancer Cluster Salzburg Paris Lodron University of Salzburg 5020 Salzburg Austria

Department of Laboratory Medicine Medical University of Vienna 1090 Vienna Austria

Department of Molecular Biotechnology and Health Sciences Molecular Biotechnology Center University of Turin 10126 Turin Italy

Department of Molecular Sciences Swedish University of Agricultural Sciences 75007 Uppsala Sweden

Department of Oncology University of Oxford Oxford OX37DQ UK

Department of Pathology Medical University Innsbruck 6020 Innsbruck Austria

Department of Pathology Medical University of Vienna 1090 Vienna Austria

Department of Pathology University of Cambridge Cambridge CB20QQ UK

Department of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center Buffalo NY 14263 USA

Department of Urology Medical University Innsbruck 6020 Innsbruck Austria

Department of Urology Medical University of Vienna 1090 Vienna Austria

Division of Nuclear Medicine Department of Biomedical Imaging and Image Guided Therapy Medical University of Vienna 1090 Vienna Austria

Division Pharmacology Department of Pharmacology Physiology and Microbiology Karl Landsteiner University of Health Sciences 3500 Krems Austria

Experimental Therapeutics Graduate Program Roswell Park Comprehensive Cancer Center Buffalo NY 14203 USA

Institute for Research in Biomedicine Università Della Svizzera Italiana 6500 Bellinzona Switzerland

Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna 1210 Vienna Austria

Institute of Human Genetics Medical University of Graz 8010 Graz Austria

Institute of Medical Genetics and Genomics Faculty of Medicine Masaryk University Kamenice 5 62500 Brno Czech Republic

Institute of Pharmacology Center for Physiology and Pharmacology Medical University of Vienna 1090 Vienna Austria

Institute of Physiology Pathophysiology and Biophysics University of Veterinary Medicine 1210 Vienna Austria

Ludwig Boltzmann Institute Applied Diagnostics 1090 Vienna Austria

MLL Munich Leukemia Laboratory 81377 Munich Germany

Molecular and Cell Biology Laboratory The Salk Institute for Biological Studies La Jolla CA 92037 USA

Patrick G Johnston Centre for Cancer Research Queen's University Belfast Belfast BT71NN UK

School of Pharmacy University of Nottingham Nottingham NG7 2RD UK

Unit for Pathology of Laboratory Animals University of Veterinary Medicine Vienna 1210 Vienna Austria

Université Paris Cité INSERM UMR S1151 CNRS UMR S8253 Institut Necker Enfants Malades 75015 Paris France

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