A distinct plasma lipid signature associated with poor prognosis in castration‐resistant prostate cancer

Abstract

Lipids are known to influence tumour growth, inflammation and chemoresistance. However, the association of circulating lipids with the clinical outcome of metastatic castration-resistant prostate cancer (CRPC) is unknown. We investigated associations between the plasma lipidome and clinical outcome in CRPC. Lipidomic profiling by liquid chromatography-tandem mass spectrometry was performed on plasma samples from a Phase 1 discovery cohort of 96 CRPC patients. Results were validated in an independent Phase 2 cohort of 63 CRPC patients. Unsupervised analysis of lipidomic profiles (323 lipid species) classified the Phase 1 cohort into two patient subgroups with significant survival differences (HR 2.31, 95% CI 1.44-3.68, p = 0.0005). The levels of 46 lipids were individually prognostic and were predominantly sphingolipids with higher levels associated with poor prognosis. A prognostic three-lipid signature was derived (ceramide d18:1/24:1, sphingomyelin d18:2/16:0, phosphatidylcholine 16:0/16:0) and was also associated with shorter survival in the Phase 2 cohort (HR 4.8, 95% CI 2.06-11.1, p = 0.0003). The signature was an independent prognostic factor when modelled with clinicopathological factors or metabolic characteristics. The association of plasma lipids with CRPC prognosis suggests a possible role of these lipids in disease progression. Further research is required to determine if therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.

Identification of Lipidomic Profiles Associated with Drug-Resistant Prostate Cancer Cells

“…Data demonstrating the significant enrichment of four lipid classes (namely, PC, PE SM, Cer) in hormone-sensitive cells in comparison to normal control cells is consistent with previous reports in plasma from prostate cancer patients [29,43,44]. Elevated concentrations of SM in plasma were previously reported in patients with PCa in comparison to the control group [45].…”

“…The elevation of PE in prostate cancer cells agrees with the findings of increased in PE in patient plasma samples [43,56], as well as in prostate cancer cells (LNCaP, 22RV1 and DU-145), as compared to PNT2 cells [44]. PE has also been detected in high abundance in exosomes derived from PC-3 cells [57].…”

Lipidomic profiling of extracellular vesicles derived from prostate and prostate cancer cell lines

“…Increased PC abundance has been identified in breast cancer, with higher levels identified in cancerous tissue compared to healthy tissue [ 44 ]. PC species have also been associated with poor prognosis, and inclusion of a PC species in a biomarker panel consisting of the lipids Cer (d18:1/24:1), SM (d18:2/16:0) and PC (16:0/16:0) had prognostic significance and this lipid signature could identify patients with poor prognosis [ 45 ]. In accordance with this three-lipid signature, the present study identified Cer (d18:1/24:1) in all samples, with lower abundance in RWPE1 (non-tumourigenic) and higher abundance in NB26 and PC-3 (tumourigenic, metastatic) EVs, suggesting a role for this ceramide in the progression of prostate cancer.…”

Association of High miR-182 Levels with Low-Risk Prostate Cancer

“… 37 Kyoto Encyclopedia of Genes and Genomes pathways enriched in the miR-182 negatively correlated genes have also been linked to aggressive PCa, including protein degradation, sphingolipid synthesis, and inflammation. 59 , 60 , 61 Interestingly, ELL2 , one of the most strongly negatively correlated genes with miR-182, induces a PIN phenotype in murine prostate when conditionally deleted, 62 and we observed high expression of miR-182 in PIN. There may be limitations to our miR-182 target-identification method, however, because several previously reported targets of miR-182 were not strongly negatively correlated with miR-182 in our data set.…”