Integration of lipidomics and transcriptomics unravels aberrant lipid metabolism and defines cholesteryl oleate as potential biomarker of prostate cancer

Abstract

In-depth delineation of lipid metabolism in prostate cancer (PCa) is significant to open new insights into prostate tumorigenesis and progression, and provide potential biomarkers with greater accuracy for improved diagnosis. Here, we performed lipidomics and transcriptomics in paired prostate cancer tumor (PCT) and adjacent nontumor (ANT) tissues, followed by external validation of biomarker candidates. We identified major dysregulated pathways involving lipogenesis, lipid uptake and phospholipids remodeling, correlated with widespread lipid accumulation and lipid compositional reprogramming in PCa. Specifically, cholesteryl esters (CEs) were most prominently accumulated in PCa, and significantly associated with cancer progression and metastasis. We showed that overexpressed scavenger receptor class B type I (SR-BI) may contribute to CEs accumulation. In discovery set, CEs robustly differentiated PCa from nontumor (area under curve (AUC) of receiver operating characteristics (ROC), 0.90–0.94). In validation set, CEs potently distinguished PCa and non-malignance (AUC, 0.84–0.91), and discriminated PCa and benign prostatic hyperplasia (BPH) (AUC, 0.90–0.96), superior to serum prostate-specific antigen (PSA) (AUC = 0.83). Cholesteryl oleate showed highest AUCs in distinguishing PCa from non-malignance or BPH (AUC = 0.91 and 0.96). Collectively, our results unravel the major lipid metabolic aberrations in PCa and imply the potential role of CEs, particularly, cholesteryl oleate, as molecular biomarker for PCa detection.

Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression

“…In particular we found reduced abundance of PCs in the EVs from PCa samples, in agreement with previously reported by Puhka and coworkers [33]. This result along with studies reporting increased abundance of PC in PCa tissue [34] could suggest that less PC-containing structures, like membrane vesicles are secreted to the extracellular environment. In addition, to the PC content, we found additional metabolites from different chemical nature differentially expressed in EVs from PCa and BPH samples that could be considered candidate biomarker for PCa including as candidate acyl carnitines, sphingomyelins, and steroids.…”

Rational Targeting of Cellular Cholesterol in Diffuse Large B-Cell Lymphoma (DLBCL) Enabled by Functional Lipoprotein Nanoparticles: A Therapeutic Strategy Dependent on Cell of Origin

“…Additionally, the high affinity HDL receptor SCARB1 was reported to be over expressed in a wide range of malignancies, including breast cancer 45 , pancreatic cancer 46 , renal cell carcinoma 47 , chronic lymphocytic leukemia 48 , and prostate cancer 9 , and has been identified as an independent prognostic factor associated with worse outcomes in breast cancer. 45 The HDL NPs are a unique cholesterol depletion agent that, due to their composition, specifically target SCARB1 17–19, 48, 49 , making them an ideal component of a cholesterol depleting therapeutic regimen.…”

“…19 However, a better understanding of the mechanism of action of HDL NPs and how this therapy can be rationally combined with other agents remains unexplored. 1, 22, 28–30 …”

Emerging roles of lipid metabolism in cancer metastasis

“…A iTRAQ-based proteomic and metabolomic analysis highlighted the critical function of fatty acid synthesis and mevalonate pathway contributing to survival of pancreatic cancer stem cells [85]. Other studies also uncovered the positive correlation between lipogenesis, lipid uptake, phospholipids remodeling and metastatic clinicopathologic features in carcinomas [86, 87]. Therefore, integrative functional multiple-omics analyses indicate that deranged lipid metabolism may confer pro-metastatic traits and accelerate the metastatic dissemination process of cancer.…”