Browsing by Author "Lhermitte, B."
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Item Open Access Characterization of the transcriptional and metabolic responses of pediatric high grade gliomas to mTOR-HIF-1a...(Impact Journals LLC, 2017-03-23) Nguyen, A.; Moussallieh, F. M.; Mackay, A.; Cicek, A. E.; Coca, A.; Chenard, M. P.; Weingertner, N.; Lhermitte, B.; Letouzé, E.; Guérin, E.; Pencreach, E.; Jannier, S.; Guenot, D.; Namer, I. J.; Jones, C.; Entz-Werlé, N.Pediatric high grade glioma (pHGGs), including sus-tentorial and diffuse intrinsic pontine gliomas, are known to have a very dismal prognosis. For instance, even an increased knowledge on molecular biology driving this brain tumor entity, there is no treatment able to cure those patients. Therefore, we were focusing on a translational pathway able to increase the cell resistance to treatment and to reprogram metabolically tumor cells, which are, then, adapting easily to a hypoxic microenvironment. To establish, the crucial role of the hypoxic pathways in pHGGs, we, first, assessed their protein and transcriptomic deregulations in a pediatric cohort of pHGGs and in pHGG’s cell lines, cultured in both normoxic and hypoxic conditions. Secondly, based on the concept of a bi-therapy targeting in pHGGs mTORC1 (rapamycin) and HIF-1α (irinotecan), we hypothesized that the balanced expressions between RAS/ERK, PI3K/AKT and HIF-1α/HIF-2α/MYC proteins or genes may provide a modulation of the cell response to this double targeting. Finally, we could evidence three protein, genomic and metabolomic profiles of response to rapamycin combined with irinotecan. The pattern of highly sensitive cells to mTOR/HIF-1α targeting was linked to a MYC/ERK/HIF-1α over-expression and the cell resistance to a major hyper-expression of HIF-2α.Item Open Access An integrated genomic and metabolomic approach for defining survival time in adult oligodendrogliomas patients(Springer, 2019) Bund, C.; Guergova‑Kuras, M.; Çiçek, A. Ercüment; Moussallieh, F.-M.; Dali‑Youcef, N.; Piotto, M.; Schneider, P.; Heller, R.; Entz‑Werle, N.; Lhermitte, B.; Chenard, M.-P.; Schott, R.; Proust, F.; Noel, G.; Namer, I. J.Introduction The identification of frequent acquired mutations shows that patients with oligodendrogliomas have divergent biology with differing prognoses regardless of histological classification. A better understanding of molecular features as well as their metabolic pathways is essential. Objectives The aim of this study was to examine the relationship between the tumor metabolome, six genomic aberrations (isocitrate dehydrogenase1 [IDH1] mutation, 1p/19q codeletion, tumor protein p53 [TP53] mutation, O6-methylguanin-DNA methyltransferase [MGMT] promoter methylation, epidermal growth factor receptor [EGFR] amplification, phosphate and tensin homolog [PTEN] methylation), and the patients’ survival time. Methods We applied 1H high-resolution magic-angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy to 72 resected oligodendrogliomas. Results The presence of IDH1, TP53, 1p19q codeletion, MGMT promoter methylation reduced the relative risk of death, whereas PTEN methylation and EGFR amplification were associated with poor prognosis. Increased concentration of 2-hydroxyglutarate (2HG), N-acetyl-aspartate (NAA), myo-inositol and the glycerophosphocholine/phosphocholine (GPC/ PC) ratio were good prognostic factors. Increasing the concentration of serine, glycine, glutamate and alanine led to an increased relative risk of death. Conclusion HRMAS NMR spectroscopy provides accurate information on the metabolomics of oligodendrogliomas, making it possible to find new biomarkers indicative of survival. It enables rapid characterization of intact tissue and could be used as an intraoperative method.Item Open Access Metabolomic characterization of human hippocampus from drug-resistant epilepsy with mesial temporal seizure(Wiley-Blackwell Publishing, 2018-03) Detour, J.; Bund, C.; Behr, C.; Cebula, H.; Çiçek, A. Ercüment; Valenti-Hirsch, Maria-Paola; Lannes, B.; Lhermitte, B.; Nehlig, A.; Kehrli, P.; Proust, F.; Hirsch, E.; Namer, Izzie-JacquesWithin a complex systems biology perspective, we wished to assess whether hippocampi with established neuropathological features have distinct metabolome. Apparently normal hippocampi with no signs of sclerosis (noHS), were compared to hippocampal sclerosis (HS) type 1 (HS1) and/or type 2 (HS2). Hippocampus metabolome from patients with epilepsy-associated neuroepithelial tumors (EANTs), namely, gangliogliomas (GGs) and dysembryoplastic neuroepithelial tumors (DNTs), was also compared to noHS epileptiform tissue. Methods: All patients underwent standardized temporal lobectomy. We applied 1H high-resolution magic angle spinning nuclear magnetic resonance (HRMAS NMR) spectroscopy to 48 resected human hippocampi. NMR spectra allowed quantification of 21 metabolites. Data were analyzed using multivariate analysis based on mutual information. Results: Clear distinct metabolomic profiles were observed between all studied groups. Sixteen and 18 expected metabolite levels out of 21 were significantly different for HS1 and HS2, respectively, when compared to noHS. Distinct concentration variations for glutamine, glutamate, and N-acetylaspartate (NAA) were observed between HS1 and HS2. Hippocampi from GG and DNT patients showed 7 and 11 significant differences in metabolite concentrations when compared to the same group, respectively. GG and DNT had a clear distinct metabolomic profile, notably regarding choline compounds, glutamine, glutamate, aspartate, and taurine. Lactate and acetate underwent similar variations in both groups. Significance: HRMAS NMR metabolomic analysis was able to disentangle metabolic profiles between HS, noHS, and epileptic hippocampi associated with EANT. HRMAS NMR metabolomic analysis may contribute to a better identification of abnormal biochemical processes and neuropathogenic combinations underlying mesial temporal lobe epilepsy.Item Open Access What does reduced FDG uptake mean in high-grade gliomas?(NLM (Medline), 2019) Bund, C.; Lhermitte, B.; Çiçek, A. Ercüment; Ruhland, E.; Proust, F.; Namer, I. J.Purpose: As well as in many others cancers, FDG uptake is correlated with the degree of malignancy in gliomas, that is, commonly high FDG uptake in high-grade gliomas. However, in clinical practice, it is not uncommon to observe high-grade gliomas with low FDG uptake. Our aim was to explore the tumor metabolism in 2 populations of high-grade gliomas presenting high or low FDG uptake. Methods: High-resolution magic-angle spinning nuclear magnetic resonance spectroscopy was realized on tissue samples from 7 high-grade glioma patients with high FDG uptake and 5 high-grade glioma patients with low FDG uptake. Tumor metabolomics was evaluated from 42 quantified metabolites and compared by network analysis. Results: Whether originating from astrocytes or oligodendrocytes, the highgrade gliomas with low FDG avidity represent a subgroup of high-grade gliomas presenting common characteristics: low aspartate, glutamate, and creatine levels, which are probably related to the impaired electron transport chain in mitochondria; high serine/glycine metabolism and so one-carbon metabolism; low glycerophosphocholine-phosphocholine ratio in membrane metabolism, which is associated with tumor aggressiveness; and finally negative MGMT methylation status. Conclusions: It seems imperative to identify this subgroup of high-grade gliomas with low FDG avidity, which is especially aggressive. Their identification could be important for early detection for a possible personalized treatment, such as antifolate treatment.