Lipidomic profiling of clinical prostate cancer reveals targetable alterations in membrane lipid composition

Lisa Butler, Chui Yan Mah, Jelle Machiels, Andrew Vincent, Swati Irani, Shadrack M. Mutuku, Xander Spotbeen, David Lynn, Wayne D. Tilley, Lisa G. Horvath, Maggie Centenera, Johannes V. Swinnen, Paul Trim

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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 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 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 first 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.
Original languageEnglish
JournalCancer Research
Publication statusPublished or Issued - 6 Aug 2021

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