Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable Alterations in Membrane Lipid Composition
Year: 2021
Type: article
Abstract: Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Herein, we used quantitative mass spectrometry to define the “lipidome” in prostate tumors with matched benign tissues (n=21), independent tissues (n=47), and primary prostate explants cultured with a clinical AR antagonist, enzalutamide (n=43). Significant differences in lipid composition were detected and spatially visualized in tumors compared to 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 PL composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting of altered tumor-related lipid features, via inhibition of acetyl CoA carboxylase 1, significantly reduced cellular proliferation in tissue explants (n=13). This first characterization of the prostate cancer lipidome in clinical tissues revealed enhanced fatty acid synthesis, elongation and desaturation as tumor-defining features, with potential for therapeutic targeting.
Source: Cancer Research
Authors: Lisa M. Butler, Chui Yan Mah, Jelle Machiels, Andrew D. Vincent, Swati Irani, Shadrack Mutuku, Xander Spotbeen, Muralidhararao Bagadi, David Waltregny, Max Moldovan, Jonas Dehairs, Frank Vanderhoydonc, Katarzyna Bloch, Rajdeep Das, Jurgen Stahl, James Kench, Thomas Gevaert, Rita Derua, Etienne Waelkens, Zeyad D. Nassar, Luke A. Selth, Paul J. Trim, Marten F. Snel, David J. Lynn, Wayne D. Tilley, Lisa G. Horvath, Margaret M. Centenera, Johannes V. Swinnen
Institutions: South Australian Health and Medical Research Institute, Freemasons Foundation Centre for Men's Health, The University of Adelaide, KU Leuven, University of Liège, Centre Hospitalier Universitaire de Liège, Northwestern University, UCL Australia, The University of Sydney, Garvan Institute of Medical Research, Royal Prince Alfred Hospital, NSW Health Pathology, Universitair Ziekenhuis Leuven, Flinders University, UNSW Sydney, Chris O’Brien Lifehouse
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Defense, Prostate Cancer Foundation, Movember Foundation, Government of South Australia, EMBL Australia, Prostate Cancer Foundation of Australia, Australian Cancer Research Foundation, National Breast Cancer Foundation, Cancer Australia, University of Adelaide, Fonds Wetenschappelijk Onderzoek, KU Leuven, Kom op tegen Kanker, Vlaamse regering, North Dakota Department of Agriculture, Medical Research Council, Australian Research Council, National Health and Medical Research Council, Cancer Council South Australia
Awards: G1173968452, G1439383451, G1920354747, Dual Targeting of the Androgen Receptor for Effective and Durable Control of Lethal Prostate Cancer, A ‘futile’ fatty acid cycle as central mediator and exploitable target in cancer resistance to molecular targeted therapy, Cell biology of the endo-/lysosomal proteostasis in cancer and neurodegeneration (LYSOCaN)., G2337106302, G2620166228, A novel strategy for targeting castrate-resistant prostate cancer, Molecular hallmarks of androgen receptor targeting in prostate cancer, Pushing AR toward better outcomes in breast and prostate cancers, G4269108088, G5289875647, G5329812878, Fatty acid elongation: a novel target for prostate cancer treatment, G6682653184, The clinical significance of sex hormone crosstalk in estrogen receptor positive breast cancer., G949189099
OpenAlex ID: W3188471663