Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM
Abstract Background Tumour cells have a high demand for arginine. However, a subset of glioblastomas has a defect in the arginine biosynthetic pathway due to epigenetic silencing of the rate limiting enzyme argininosuccinate synthetase (ASS1). These tumours are auxotrophic for arginine and susceptib...
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doaj-284c84f10abc44169584836fd2f255df2020-11-24T23:21:22ZengBMCBMC Cancer1471-24072018-02-0118111610.1186/s12885-018-4040-3Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBMLina Mörén0Richard Perryman1Tim Crook2Julia K. Langer3Kevin Oneill4Nelofer Syed5Henrik Antti6Department of Chemistry, Umeå UniversityJohn Fulcher Neuro-Oncology Laboratory, Imperial College LondonSt Luke’s Cancer Centre, Royal Surrey County HospitalJohn Fulcher Neuro-Oncology Laboratory, Imperial College LondonJohn Fulcher Neuro-Oncology Laboratory, Imperial College LondonJohn Fulcher Neuro-Oncology Laboratory, Imperial College LondonDepartment of Chemistry, Umeå UniversityAbstract Background Tumour cells have a high demand for arginine. However, a subset of glioblastomas has a defect in the arginine biosynthetic pathway due to epigenetic silencing of the rate limiting enzyme argininosuccinate synthetase (ASS1). These tumours are auxotrophic for arginine and susceptible to the arginine degrading enzyme, pegylated arginine deiminase (ADI-PEG20). Moreover, ASS1 deficient GBM have a worse prognosis compared to ASS1 positive tumours. Since altered tumour metabolism is one of the hallmarks of cancer we were interested to determine if these two subtypes exhibited different metabolic profiles that could allow for their non-invasive detection as well as unveil additional novel therapeutic opportunities. Methods We looked for basal metabolic differences using one and two-dimensional gas chromatography-time-of-flight mass spectrometry (1D/2D GC-TOFMS) followed by targeted analysis of 29 amino acids using liquid chromatography-time-of-flight mass spectrometry (LC-TOFMS). We also looked for differences upon arginine deprivation in a single ASS1 negative and positive cell line (SNB19 and U87 respectively). The acquired data was evaluated by chemometric based bioinformatic methods. Results Orthogonal partial least squares-discriminant analysis (OPLS-DA) of both the 1D and 2D GC-TOFMS data revealed significant systematic difference in metabolites between the two subgroups with ASS1 positive cells generally exhibiting an overall elevation of identified metabolites, including those involved in the arginine biosynthetic pathway. Pathway and network analysis of the metabolite profile show that ASS1 negative cells have altered arginine and citrulline metabolism as well as altered amino acid metabolism. As expected, we observed significant metabolite perturbations in ASS negative cells in response to ADI-PEG20 treatment. Conclusions This study has highlighted significant differences in the metabolome of ASS1 negative and positive GBM which warrants further study to determine their diagnostic and therapeutic potential for the treatment of this devastating disease.http://link.springer.com/article/10.1186/s12885-018-4040-3GlioblastomaEpigeneticsASS1ArginineADI-PEG20Metabolomics |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lina Mörén Richard Perryman Tim Crook Julia K. Langer Kevin Oneill Nelofer Syed Henrik Antti |
spellingShingle |
Lina Mörén Richard Perryman Tim Crook Julia K. Langer Kevin Oneill Nelofer Syed Henrik Antti Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM BMC Cancer Glioblastoma Epigenetics ASS1 Arginine ADI-PEG20 Metabolomics |
author_facet |
Lina Mörén Richard Perryman Tim Crook Julia K. Langer Kevin Oneill Nelofer Syed Henrik Antti |
author_sort |
Lina Mörén |
title |
Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM |
title_short |
Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM |
title_full |
Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM |
title_fullStr |
Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM |
title_full_unstemmed |
Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM |
title_sort |
metabolomic profiling identifies distinct phenotypes for ass1 positive and negative gbm |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2018-02-01 |
description |
Abstract Background Tumour cells have a high demand for arginine. However, a subset of glioblastomas has a defect in the arginine biosynthetic pathway due to epigenetic silencing of the rate limiting enzyme argininosuccinate synthetase (ASS1). These tumours are auxotrophic for arginine and susceptible to the arginine degrading enzyme, pegylated arginine deiminase (ADI-PEG20). Moreover, ASS1 deficient GBM have a worse prognosis compared to ASS1 positive tumours. Since altered tumour metabolism is one of the hallmarks of cancer we were interested to determine if these two subtypes exhibited different metabolic profiles that could allow for their non-invasive detection as well as unveil additional novel therapeutic opportunities. Methods We looked for basal metabolic differences using one and two-dimensional gas chromatography-time-of-flight mass spectrometry (1D/2D GC-TOFMS) followed by targeted analysis of 29 amino acids using liquid chromatography-time-of-flight mass spectrometry (LC-TOFMS). We also looked for differences upon arginine deprivation in a single ASS1 negative and positive cell line (SNB19 and U87 respectively). The acquired data was evaluated by chemometric based bioinformatic methods. Results Orthogonal partial least squares-discriminant analysis (OPLS-DA) of both the 1D and 2D GC-TOFMS data revealed significant systematic difference in metabolites between the two subgroups with ASS1 positive cells generally exhibiting an overall elevation of identified metabolites, including those involved in the arginine biosynthetic pathway. Pathway and network analysis of the metabolite profile show that ASS1 negative cells have altered arginine and citrulline metabolism as well as altered amino acid metabolism. As expected, we observed significant metabolite perturbations in ASS negative cells in response to ADI-PEG20 treatment. Conclusions This study has highlighted significant differences in the metabolome of ASS1 negative and positive GBM which warrants further study to determine their diagnostic and therapeutic potential for the treatment of this devastating disease. |
topic |
Glioblastoma Epigenetics ASS1 Arginine ADI-PEG20 Metabolomics |
url |
http://link.springer.com/article/10.1186/s12885-018-4040-3 |
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