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TCA cycle metabolomics of H3K27M Cell Nucleus Fraction and Cell Mitonchonrdial Fraction (Part-IV)

ABSTRACT: Testing TCA concentrations of Diffuse Intrinsic Pontine Gliomas (DIPG) cellines with H3K27M mutations. Preliminary studies show H3K27M tumor cells are addicted to Gln for survival. Removal of Gln from media resulted in tumor cell death which was rescued by the addition of α-KG. These data show that Gln is taken up and metabolized by H3K27M tumor cells and that Gln derived α-KG is critical for the survival of these tumors. Interestingly, tumor cell death with Gln deprivation was similar to the effect of the JMJD3 inhibitor GSKJ4. Therefore, Gln derived α-KG may be required for both anaplerosis and to drive JMJD3 demethylation. We hypothesize that H3K27M tumors are reliant on α-KG that is derived from Gln to drive the TCA cycle and further decrease H3K27 methylation levels. Furthermore, inhibition of Gln metabolism may represent a novel therapeutic approach for tumors with this mutation. In this study, TCA cycle metabolomics are analyzed of H3K27M cells grown in regular glutamine media, glutamine free media, and glutamine free media with alpha-ketoglutarate. Additionally, cell nucleus and cell mitochrondial fractions are run separately.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Glioma Cells

DISEASE(S): Cancer

SUBMITTER: David Daniels

PROVIDER: ST001026 | MetabolomicsWorkbench | Wed Jul 18 00:00:00 BST 2018

REPOSITORIES: MetabolomicsWorkbench

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Project description:Glutamine (Gln) metabolism has been reported to play an essential role in cancer. However, a comprehensive analysis of its role in lung adenocarcinoma is still unavailable. This study established a novel system of quantification of Gln metabolism to predict the prognosis and immunotherapy efficacy in lung cancer. Further, the Gln metabolism in tumor microenvironment (TME) was characterized and the Gln metabolism-related genes were identified for targeted therapy. We comprehensively evaluated the patterns of Gln metabolism in 513 patients diagnosed with lung adenocarcinoma (LUAD) based on 73 Gln metabolism-related genes. Based on differentially expressed genes (DEGs), a risk model was constructed using Cox regression and Lasso regression analysis. The prognostic efficacy of the model was validated using an individual LUAD cohort form Shandong Provincial Hospital, an integrated LUAD cohort from GEO and pan-cancer cohorts from TCGA databases. Five independent immunotherapy cohorts were used to validate the model performance in predicting immunotherapy efficacy. Next, a series of single-cell sequencing analyses were used to characterize Gln metabolism in TME. Finally, single-cell sequencing analysis, transcriptome sequencing, and a series of in vitro experiments were used to explore the role of EPHB2 in LUAD. Patients with LUAD were eventually divided into low- and high-risk groups. Patients in low-risk group were characterized by low levels of Gln metabolism, survival advantage, “hot” immune phenotype and benefit from immunotherapy. Compared with other cells, tumor cells in TME exhibited the most active Gln metabolism. Among immune cells, tumor-infiltrating T cells exhibited the most active levels of Gln metabolism, especially CD8 T cell exhaustion and Treg suppression. EPHB2, a key gene in the model, was shown to promote LUAD cell proliferation, invasion and migration, and regulated the Gln metabolic pathway. Finally, we found that EPHB2 was highly expressed in macrophages, especially M2 macrophages. It may be involved in the M2 polarization of macrophages and mediate the negative regulation of M2 macrophages in NK cells. This study revealed that the Gln metabolism-based model played a significant role in predicting prognosis and immunotherapy efficacy in lung cancer. We further characterized the Gln metabolism of TME and investigated the Gln metabolism-related gene EPHB2 to provide a theoretical framework for anti-tumor strategy targeting Gln metabolism.

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TCA cycle metabolomics of H3K27M Cell Nucleus Fraction and Cell Mitonchonrdial Fraction (Part-IV)

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