Background. Codeletion of chromosome arms 1p and 19q (1p/19q codeletion) highly benefits diagnosis and prognosis in gliomas. In this study, we investigated the effect of 1p/19q codeletion on cancer cell metabolism and evaluated possible metabolic targets for tailored therapies. Methods. We combined in vivo 1H (proton) magnetic resonance spectroscopy (MRS) measurements in human gliomas with the analysis of a series of standard amino acids by liquid chromatography-mass spectroscopy ( LC-MS) in human glioma biopsies. Sixty-five subjects with low-grade glioma were included in the study: 31 underwent the MRI/MRS examination, 47 brain tumor tissue samples were analyzed with LC-MS, and 33 samples were analyzed for gene expression with quantitative PCR. Additionally, we performed metabolic tracer experiments in cell models with 1p deletion. Results. We report the first in vivo detection of cystathionine by MRS in 1p/19q codeleted gliomas. Selective accumulation of cystathionine was observed in codeleted gliomas in vivo, in brain tissue samples, as well as in cells harboring heterozygous deletions for serine-and cystathionine-pathway genes located on 1p: phosphoglycerate dehydrogenase (PHGDH) and cystathionine gamma-lyase (CTH). Quantitative PCR analyses showed 40-50% lower expression of both PHGDH and CTH in 1p/19q codeleted gliomas compared with their non-codeleted counterparts. Conclusions. Our results provide strong evidence of a selective vulnerability of codeleted gliomas to serine and glutathione depletion and point to cystathionine as a possible noninvasive marker of treatment response.
Bibliographical noteFunding Information:
FB and SL acknowledge support from the program “Investissements d’avenir” ANR-11-INBS-0011—NeurATRIS: Translational Research Infrastructure for Biotherapies in Neurosciences, ANR-10-IAIHU-06—Paris Institute of Translational neuroscience, and ANR-11-INBS-0006—France Life Imaging. ALDS and MS acknowledge support from the grant INCa-DGOS-Inserm_1250 of the SiRIC CURAMUS. ALDS and MS acknowledge support from the Institut National de la Santé et de la Recherche Médicale grant: INCa-DGOSInserm_1250 (SiRIC CURAMUS). DD and MM acknowledge support from the following National Institutes of Health grants: BTRC P41 EB015894 and P30 NS076408.