[en] Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues (n = 21), independent unmatched tissues (n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide (n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting. SIGNIFICANCE: This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.
Disciplines :
Urology & nephrology
Author, co-author :
Butler, Lisa M ; Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia. lisa.butler@adelaide.edu.au ; South Australian Health and Medical Research Institute, Adelaide, Australia
Mah, Chui Yan ; Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia ; South Australian Health and Medical Research Institute, Adelaide, Australia
Machiels, Jelle; Laboratory of Lipid Metabolism and Cancer, LKI - Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Vincent, Andrew D; Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia ; South Australian Health and Medical Research Institute, Adelaide, Australia
Irani, Swati; Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia ; South Australian Health and Medical Research Institute, Adelaide, Australia
Mutuku, Shadrack M; Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia ; South Australian Health and Medical Research Institute, Adelaide, Australia
Spotbeen, Xander ; South Australian Health and Medical Research Institute, Adelaide, Australia ; Laboratory of Lipid Metabolism and Cancer, LKI - Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Bagadi, Muralidhararao; Laboratory of Lipid Metabolism and Cancer, LKI - Leuven Cancer Institute, KU Leuven, Leuven, Belgium
WALTREGNY, David ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'urologie
Moldovan, Max ; South Australian Health and Medical Research Institute, Adelaide, Australia
Dehairs, Jonas; Laboratory of Lipid Metabolism and Cancer, LKI - Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Vanderhoydonc, Frank; Laboratory of Lipid Metabolism and Cancer, LKI - Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Bloch, Katarzyna; Laboratory of Lipid Metabolism and Cancer, LKI - Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Das, Rajdeep; Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia ; Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, Australia ; Northwestern University, Feinberg School of Medicine, Comprehensive Transplant Center, Chicago, Illinois
Stahl, Jurgen; Clinpath Laboratories, Adelaide, Australia
Kench, James G ; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, NSW Health Pathology, Camperdown, New South Wales, Australia ; Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia ; University of Sydney, Camperdown, New South Wales, Australia
Gevaert, Thomas; Department of Urology, UZ Leuven, Leuven, Belgium
Derua, Rita; Department of Cellular and Molecular Medicine and SyBioMa Center, KU Leuven, Leuven, Belgium
Waelkens, Etienne; Department of Cellular and Molecular Medicine and SyBioMa Center, KU Leuven, Leuven, Belgium
Nassar, Zeyad D ; Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia ; South Australian Health and Medical Research Institute, Adelaide, Australia
Selth, Luke A ; Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia ; Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, Australia ; Flinders Health and Medical Research Institute, Flinders University, Adelaide, Australia
Trim, Paul J ; South Australian Health and Medical Research Institute, Adelaide, Australia
Snel, Marten F ; South Australian Health and Medical Research Institute, Adelaide, Australia
Lynn, David J ; South Australian Health and Medical Research Institute, Adelaide, Australia ; Flinders Health and Medical Research Institute, Flinders University, Adelaide, Australia
Tilley, Wayne D ; Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia ; Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, Australia
Horvath, Lisa G; Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia ; University of Sydney, Camperdown, New South Wales, Australia ; Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia ; University of New South Wales, Sydney, New South Wales, Australia
Centenera, Margaret M; Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia ; South Australian Health and Medical Research Institute, Adelaide, Australia
Swinnen, Johannes V ; Laboratory of Lipid Metabolism and Cancer, LKI - Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Movember Foundation PCFA - Prostate Cancer Foundation of Australia USDOD - United States Department of Defense NHMRC - National Health and Medical Research Council Cancer Australia ACRF - Australian Cancer Research Foundation EMBL Australia
Funding text :
L.M. Butler reports grants from Movember Foundation, Prostate Cancer Foundation of Australia, U.S. Department of Defense, Cancer Council South Australia, and Cancer Australia during the conduct of the study. J. Machiels reports a patent for WO2012038525 licensed. E. Waelkens reports grants from European Community during the conduct of the study. L.A. Selth reports grants from Cancer Council SA and Movember/Prostate Cancer Foundation of Australia during the conduct of the study. P.J. Trim reports other support from University of Adelaide during the conduct of the study. M.F. Snel reports other support from University of Adelaide (L.M. Butler, main author) during the conduct of the study. L.G. Horvath reports other support from Exelexis, MSD, Pfizer, Eli-Lilly, Amgen, Novartis, Bristol Myers Squibb, Beigene, and Antagene outside the submitted work. M.M. Centenera reports grants from Prostate Cancer Foundation of Australia and Movember Foundation during the conduct of the study. J.V. Swinnen reports grants from The Movember Foundation/Prostate Cancer Foundation of Australia, Research Foundation - Flanders, Stichting tegen Kanker, Interreg V-A EMR23 "EURLIPIDS," Kom op tegen kanker, and Fondation Fournier-Majoie pour l’Innovation; grants and other support from KU Leuven during the conduct of the study; in addition, J.V. Swinnen has a patent for phospholipid profiling issued. No disclosures were reported by the other authors.This research was supported by The Movember Foundation/Prostate Cancer Foundation of Australia (MRTA3); The Prostate Cancer Foundation of Australia (NDDA-4711); The U.S. Department of Defense (PC180582); The National Health and Medical Research Council (NHMRC) of Australia (1121057, 1130077, 1138242, 1145777); Cancer Australia (1138766); the Australian Cancer Research Foundation (Centre for Integrated Cancer Systems Biology); a Movember/NBCF Collaborative Linkage Grant (MNBCF-17-012), KU Leuven grants C1 (C16/15/073) and C3 (C32/ 17/052); Research Foundation - Flanders (FWO) grants G.841.15 and G0E0817N; Interreg V-A EMR23 EURLIPIDS; Stichting tegen Kanker; Kom op tegen Kanker; and the Fondation Fournier-Majoie pour l’Innovation. L.M. Butler was supported by a Future Fellowship from the Australian Research Council (FT130101004), and L.M. Butler and L.A. Selth are supported by Principal Cancer Research Fellowships (PRF1117 and PRF2919, respectively) awarded by Cancer Council’s Beat Cancer project on behalf of its donors, the state Government through the Department of Health and the Australian Government through the Medical Research Future Fund. C.Y. Mah, R. Das, and S.M. Mutuku were supported by PhD Scholarships from theThis research was supported by The Movember Foundation/Prostate Cancer Foundation of Australia (MRTA3); The Prostate Cancer Foundation of Australia (NDDA-4711); The U.S. Department of Defense (PC180582); The National Health and Medical Research Council (NHMRC) of Australia (1121057, 1130077, 1138242, 1145777); Cancer Australia (1138766); the Australian Cancer Research Foundation (Centre for Integrated Cancer Systems Biology); a Movember/NBCF Collaborative Linkage Grant (MNBCF-17-012), KU Leuven grants C1 (C16/15/073) and C3 (C32/ 17/052); Research Foundation - Flanders (FWO) grants G.841.15 and G0E0817N; Interreg V-A EMR23 EURLIPIDS; Stichting tegen Kanker; Kom op tegen Kanker; and the Fondation Fournier-Majoie pour l?Innovation. L.M. Butler was supported by a Future Fellowship from the Australian Research Council (FT130101004), and L.M. Butler and L.A. Selth are supported by Principal Cancer Research Fellowships (PRF1117 and PRF2919, respectively) awarded by Cancer Council?s Beat Cancer project on behalf of its donors, the state Government through the Department of Health and the Australian Government through the Medical Research Future Fund. C.Y. Mah, R. Das, and S.M. Mutuku were supported by PhD Scholarships from the University of Adelaide, and C.Y. Mah and R. Das received Top-Up Scholarships from the Freemasons Centre for Male Health and Wellbeing at the University of Adelaide; Z.D. Nassar is supported by an Early Career Fellowship from the National Health and Medical Research Council of Australia (1138648); X. Spotbeen is supported by a Fellowship from the Research Foundation Flanders (FWO); D.J. Lynn is supported by an EMBL Australia group leader award; L.G. Horvath is supported by an Investigator Award from the National Health and Medical Research Council of Australia (1196225). The authors are grateful to the Belgian and Australian study participants, as well as the urologists, nurses, and histopathologists who assisted in the recruitment and collection of patient samples and clinical information.
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