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Effect of systemic depletion of glutamine via PEGylated glutaminase on CT26 tumor tissue.

ABSTRACT: Proliferating cancer cells are addicted to glutamine for biomass synthesis and energy generation. We here enzymatically deplete circulating glutamine in mice and report how cancer cells adapt to low circulating glutamine and document immunological changes in the tumor microenvironment (TME) upon glutamine depletion in CT26 tumor model. We show that cancer cells adapt to low glutamine by diverting intracellular glutamine flux to nucleotide synthesis and downregulating global translation. Through immune cell deconvolution and GSEA, we show that systemic glutamine depletion is immunsosuppressive and marked by accumulaton of PMN-MDSC in the TME.

ORGANISM(S): Mus musculus

PROVIDER: GSE247472 | GEO | 2024/04/16

REPOSITORIES: GEO

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Effect of systemic depletion of glutamine via PEGylated glutaminase on CT26 tumor tissue.

Project description:Effect of systemic depletion of glutamine via PEGylated glutaminase on CT26 tumor tissue.

| PRJNA1038746 | ENA

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Inhibiting MYC-regulated Glutaminase Metabolic Axis is an Effective Synthetic Lethal Approach for Treating Chemoresistant Cancers

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2020-07-23 | GSE154941 | GEO

Glutaminase C N-terminus phosphorylation decreases its enzymatic activity

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Project description:Triple-negative breast cancer (TNBC) relies on glutamine uptake by the transporter ASCT2 to sustain their unique glutamine metabolism and growth. Despite previous data showing cell growth inhibition after ASCT2 knockdown, ASCT2 CRISPR knockout was well-tolerated by breast cancer cell lines. Despite the loss of a glutamine transporter and low rate of glutamine uptake, intracellular glutamine steady state levels were higher in ASCT2 knockout compared to control TNBC cells. Proteomics data revealed upregulation of macropinocytosis, reduction in glutamine efflux and glutamine synthesis in ASCT2 knockout cells. Loss of ASCT2 in TNBC cell line HCC1806 induced a 5-10-fold increase in macropinocytosis across 5 separate ASCT2 knockout clones, compared to a modest 2-fold increase in the shRNA ASCT2 knockdown. By comparison, ASCT2 knockout impaired cell proliferation in a non-macropinocytic breast cancer cell line, HCC1569. These data suggest that macropinocytosis provides a novel resistance mechanism to strategies targeting glutamine uptake alone. Despite this adaptation, TNBC cells continue to rely on glutamine metabolism for their growth, which suggests therapeutic targeting may need to focus on downstream glutamine metabolism pathways.

2024-09-15 | GSE256218 | GEO

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Project description:Cancer cells can metabolize glutamine to replenish TCA cycle intermediates, leading to a dependence on glutaminolysis for cell survival. However, a mechanistic understanding of the role that glutamine metabolism has on the survival of glioblastoma (GBM) brain tumor stem cells (BTSCs) has not yet been elucidated. Here we report that, across a panel of twenty glioblastoma BTSC lines, glutaminase (GLS) inhibition showed a variable response – from complete blockade of cell growth to absolute resistance. Surprisingly, BTSC sensitivity to GLS inhibition was a result of reduced intracellular glutamate triggering the amino acid deprivation response (AADR) and not due to the contribution of glutaminolysis to the TCA cycle. Moreover, BTSC sensitivity to GLS inhibition negatively correlated with the expression of the astrocytic glutamate transporters EAAT1 and EAAT2. Blocking glutamate transport in BTSCs with high EAAT1/EAAT2 expression rendered these cells susceptible to GLS inhibition, triggering the AADR, and limiting cell growth. These findings uncover a unique metabolic vulnerability in BTSCs, support the therapeutic targeting of the upstream activators and downstream effectors of the AADR pathway in GBM, and demonstrate that gene expression patterns reflecting the cellular hierarchy of the tissue of origin can alter the metabolic requirements of the cancer stem cell population.

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Differential Regulation of Th17 and Th1 Cells in mouse by Glutaminase-Dependent Metabolism and Chromatin Remodeling

Project description:Activated T cells differentiate into functional subsets which require distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to provide substrate for the tricarboxylic acid cycle and epigenetic reactions and here we identify a key role for GLS in T cell activation and specification. Though GLS-deficiency diminished T cell activation, proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet and Interferon-γ expression and CD4 Th1 and CD8 CTL effector cell differentiation. These changes were mediated by differentially altered gene expression and chromatin accessibility, leading to increased sensitivity of Th1 cells to IL-2 mediated mTORC1 signaling. In vivo, GLS-null T cells failed to drive a Th17 mediated Graft-vs-Host Disease model. Transient inhibition of GLS, however, increased Th1 and CTL T cell numbers in viral and chimeric antigen receptor models. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.

2018-09-01 | E-MTAB-6648 | biostudies-arrayexpress

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