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Combined transcriptomic and lipidomic analysis reveals aberrant lipid metabolism in central nervous system hemangioblastomas.

ABSTRACT: Peritumoral cysts are commonly detected in the central nervous system tumors, especially hemangioblastomas (HBs). However, the molecular mechanisms driving their formation and propagation are still unknown. We conducted an integrated lipidomics and transcriptomics analysis on solid and cystic HB samples in order to elucidate the changes in the lipid profile and expression of lipid metabolism-related genes during cyst formation. Transcriptomic analysis revealed differential expression of several genes between the solid and cystic HBs, and those associated with lipid metabolism, such as ADCY4, MGLL, ACOT2, DGKG, SHC1 and LPAR2, were markedly dysregulated in the cystic HBs. The lipidomic analysis further showed a significant reduction in the abundance of triacylglycerol, ceramide, lysophosphatidylcholine and lysophosphatidylethanolamine, and an increase in phosphatidylcholine and phosphatidylethanolamine levels in the cystic HBs. Furthermore, bioinformatics analysis revealed altered lipid biosynthesis, glycerophospholipid metabolism and phospholipase activity in the cystic HBs. Taken together, our findings indicate that cyst formation in HBs is related with aberrant lipid metabolism.

SUBMITTER: Wang Q

PROVIDER: S-EPMC7809491 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Combined transcriptomic and lipidomic analysis reveals aberrant lipid metabolism in central nervous system hemangioblastomas.

Wang Qiguang Q Liu Wenke W Zhang Si S Liang Zuoyu Z Jiang Linhong L Xue Aiqin A Cen Xiaobo X Bu Qian Q

Scientific reports 20210114 1

Peritumoral cysts are commonly detected in the central nervous system tumors, especially hemangioblastomas (HBs). However, the molecular mechanisms driving their formation and propagation are still unknown. We conducted an integrated lipidomics and transcriptomics analysis on solid and cystic HB samples in order to elucidate the changes in the lipid profile and expression of lipid metabolism-related genes during cyst formation. Transcriptomic analysis revealed differential expression of several ...[more]

PMID: 33446752

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Project description:Hemangioblastomas (HBs) of the central nervous system are highly vascular neoplasms that occur sporadically or as a manifestation of von Hippel-Lindau (VHL) disease. Despite their benign nature, HBs are clinically heterogeneous and can be associated with significant morbidity due to mass effects of peritumoral cysts or tumor progression. Underlying molecular factors involved in HB tumor biology remain elusive. We investigated genome-wide DNA methylation profiles and clinical and histopathological features in a series of 47 HBs from 42 patients, including 28 individuals with VHL disease. Thirty tumors occurred in the cerebellum, 8 in the brainstem and 8 HBs were of spinal location, while 1 HB was located in the cerebrum. Histologically, 12 HBs (26%) belonged to the cellular subtype and exclusively occurred in the cerebellum, whereas 35 HBs were reticular (74%). Unsupervised clustering and dimensionality reduction of DNA methylation profiles revealed two distinct subgroups. Methylation cluster 1 comprised 30 HBs of mainly cerebellar location (29/30, 97%), whereas methylation cluster 2 contained 17 HBs predominantly located in non-cerebellar compartments (16/17, 94%). The sum of chromosomal regions being affected by copy-number alterations was significantly higher in methylation cluster 1 compared to cluster 2 (mean 262 vs. 109 Mb, p = 0.001). Of note, loss of chromosome 6 occurred in 9/30 tumors (30%) of methylation cluster 1 and was not observed in cluster 2 tumors (p = 0.01). No relevant methylation differences between sporadic and VHL-related HBs or cystic and non-cystic HBs could be detected. Deconvolution of the bulk DNA methylation profiles revealed four methylation components that were associated with the two methylation clusters suggesting cluster-specific cell-type compositions. In conclusion, methylation profiling of HBs reveals 2 distinct subgroups that mainly associate with anatomical location, cytogenetic profiles and differences in cell type composition, potentially reflecting different cells of origin.

Project description:In this study two regions of embryonic (E11) mouse central nervous system (CNS) have been profiled for their unesterified sterol content. Using high-performance liquid chromatography (HPLC)-mass spectrometry (MS) and tandem mass spectrometry (MS(n)) low levels of oxysterols (estimated 2-165 ng g(-1) wet weight) were identified in cortex (Ctx) and spinal cord (Sc). The identified oxysterols include 7 alpha-, 7 beta-, 22R-, 24S-, 25- and 27-hydroxycholesterol; 24,25- and 24,27-dihydroxycholesterol; and 24S,25-epoxycholesterol. Of these, 24S-hydroxycholesterol is biosynthesised exclusively in brain. In comparison to adult mouse where the 24S-hydroxycholesterol level is about 40 microg g(-1) in brain the level of 24S-hydroxycholesterol reported here (estimated 26 ng g(-1) in Ctx and 13 ng g(-1) in Sc) is extremely low. Interestingly, the level of 24S,25-epoxycholesterol in both CNS regions (estimated 165 ng g(-1) in Ctx and 91 ng g(-1) in Sc) is somewhat higher than the levels of the hydroxycholesterols. This oxysterol is formed in parallel to cholesterol via a shunt of the mevalonate pathway and its comparatively high abundance may be a reflection of a high rate of cholesterol synthesis at this stage of development. Levels of cholesterol (estimated 1.25 mg g(-1) in Ctx and 1.15 mg g(-1) in Sc) and its precursors were determined by gas chromatography-mass spectrometry (GC-MS). In both CNS regions cholesterol levels were found to be lower than those reported in the adult, but in relation to cholesterol the levels of cholesterol precursors were higher than found in adult indicating a high rate of cholesterol synthesis. In summary, our data provide evidence for the presence of endogenous oxysterols in two brain regions of the developing CNS. Moreover, while most of the enzymes involved in hydroxysterol synthesis are minimally active at E11, our results suggest that the mevalonate pathway is significantly active, opening up the possibility for a function of 24S,25-epoxycholesterol during brain development.

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Combined transcriptomic and lipidomic analysis reveals aberrant lipid metabolism in central nervous system hemangioblastomas.

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Combined transcriptomic and lipidomic analysis reveals aberrant lipid metabolism in central nervous system hemangioblastomas.

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