Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable Alterations in Membrane Lipid Composition

Abstract

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.

Multi-Omics Prognostic Signatures Based on Lipid Metabolism for Colorectal Cancer

“…Ran et al emphasized that the exposure of PS in tumor cells was induced by oxidative stress and cytokines, and the exposed PS binding to immune cells regulated the immune infiltrations and biological process of tumor cells (Ran and Thorpe, 2002). Previous studies have shown that fatty acid chain elongation, one of the characteristics of malignant tumors, was represented by PS in prostate cancer (Butler et al, 2021). In CRC, Jiřina et al utilized LC-MS to determine phospholipid components, including phosphatidylserine as the biological markers to distinguish normal colorectal epithelial cells from CRC cells.…”

Personalized Medicine for Prostate Cancer: Is Targeting Metabolism a Reality?

“…Similarly, 2,4-dienoyl-CoA reductase (DECR1) and enoyl-CoA delta isomerase 2 (ECI2), auxiliary enzymes responsible for the degradation of unsaturated fatty acids, are also essential for prostate cancer growth and therapy resistance (84)(85)(86). Finally, studies using tandem mass spectrometry lipidomics have reported marked alterations in the prostate lipidome with cancer (38,82,87,88), indicating the likelihood that other nodes of lipid metabolism are regulated in prostate cancer development and metastasis.…”

“…Moreover, several drugs that target other enzymes in the de novo lipogenesis pathway are in clinical trials for other diseases, such as the ACC inhibitors Firsocostat (Gilead) and PF-05175157 (Pfizer) for non-alcoholic fatty liver disease (145), and derivatives of these compounds could conceivably be adopted for treatment of prostate cancer. Indeed, PF-05175157 showed promising results in reducing proliferation and inducing apoptosis in localized prostate cancer patient-derived explants (88).…”

Harnessing the Utility of Ex Vivo Patient Prostate Tissue Slice Cultures

“…revealed that the castration response of TS grafted into mice mimicked the expression of proteins in prostate specimens from patients with androgen deprivation therapies ( 9 ). The patient heterogeneity of anti-proliferation responses to bicalutamide and enzalutamide was demonstrated in PDE ( 17 , 18 ). Butler et al.…”

“…Butler et al. further showed tumor areas resistant to enzalutamide also had aberrations in their lipid profiles ( 18 ), which lead to discovery of ELOVL5, a fatty acid elongase, as a new metabolic target of androgens ( 24 ). The potential to predict patient response to combination therapy with enzalutamide and docetaxel was shown in PDE, reflecting individual treatment outcomes observed in the clinic ( 21 ).…”