15
IRUS Total
Downloads
  Altmetric

Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM

Title: Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM
Authors: Moren, L
Perryman, R
Crook, T
Langer, JK
Oneill, K
Syed, N
Antti, H
Item Type: Journal Article
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.
Issue Date: 8-Feb-2018
Date of Acceptance: 23-Jan-2018
URI: http://hdl.handle.net/10044/1/82276
DOI: 10.1186/s12885-018-4040-3
ISSN: 1471-2407
Publisher: BioMed Central
Start Page: 1
End Page: 16
Journal / Book Title: BMC Cancer
Volume: 18
Copyright Statement: © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: Barrow Foundation UK
Brain Tumour Research Campaign
Brain Tumour Research
Funder's Grant Number: N/A
N/A
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Glioblastoma
Epigenetics
ASS1
Arginine
ADI-PEG20
Metabolomics
Chemometrics
ARGININE-DEPENDENT CANCERS
ACUTE MYELOID-LEUKEMIA
ARGININOSUCCINATE SYNTHETASE
GLIOBLASTOMA-MULTIFORME
HEPATOCELLULAR-CARCINOMA
DEPRIVATION
PATHWAY
GLIOMA
ASPARAGINASE
MESOTHELIOMA
ADI-PEG20
ASS1
Arginine
Chemometrics
Epigenetics
Glioblastoma
Metabolomics
Argininosuccinate Synthase
Brain Neoplasms
Cell Line, Tumor
Glioblastoma
Humans
Metabolomics
Phenotype
Cell Line, Tumor
Humans
Glioblastoma
Brain Neoplasms
Argininosuccinate Synthase
Phenotype
Metabolomics
Science & Technology
Life Sciences & Biomedicine
Oncology
Glioblastoma
Epigenetics
ASS1
Arginine
ADI-PEG20
Metabolomics
Chemometrics
ARGININE-DEPENDENT CANCERS
ACUTE MYELOID-LEUKEMIA
ARGININOSUCCINATE SYNTHETASE
GLIOBLASTOMA-MULTIFORME
HEPATOCELLULAR-CARCINOMA
DEPRIVATION
PATHWAY
GLIOMA
ASPARAGINASE
MESOTHELIOMA
Oncology & Carcinogenesis
1112 Oncology and Carcinogenesis
1117 Public Health and Health Services
Publication Status: Published
Article Number: ARTN 167
Online Publication Date: 2018-02-08
Appears in Collections:Department of Brain Sciences



This item is licensed under a Creative Commons License Creative Commons