Myeloid amino acid metabolism supports solid tumor malignancy
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ABSTRACT:
PROVIDER: PRJNA518914 | ENA |
REPOSITORIES: ENA
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Project description:Cancer immunosuppression involves cellular pathways appropriated by tumors to escape immune surveillance but are normally required for tissue homeostasis and repair, self-tolerance, and successful transplantation. Among these pathways, enzymes that degrade tryptophan and arginine are thought to suppress activated T cells in the tumor microenvironment and are therefore attractive drug targets. However, how amino acid metabolism controls the development and progression of cancer has remained elusive, since commonly used implantable tumor models may not faithfully recapitulate the complex cellular and biochemical interactions within tumor microenvironments. To address this, we generated a novel, penetrant autochthonous model of neuroblastoma to accurately quantify tumor growth non-invasively and simultaneously genetically manipulate the enzymes that mediate tryptophan and arginine metabolism, and the cells that express them. We established that tumor development and growth were dependent on infiltrating CCR2+ bone marrow-derived myeloid cells but independent of Stat6-dependent ‘M2’ macrophages. Macrophages can modulate CD4+ T cell activation, proliferation, and differentiation by consuming amino acids and forcing the T cells to remain in the G1 phase of the cell cycle. Indeed, we found that CD4+ T cells deprived of arginine increased Foxp3 expression and adopted a unique regulatory-like phenotype. Notably, depletion of CD4+ T cells like CCR2+ macrophages, virtually eliminated tumor formation. When rare tumors did form in CD4-depleted mice, they contained Foxp3+ CD8 T cells, suggesting regulatory T cell activity is a fundamental requirement for tumor development. When we ablated macrophage arginase 1 (Arg1), an enzyme that locally consumes arginine, in the tumor-prone background, almost no tumors were observed. Therefore, Arg1 and arginine metabolism form a pro-tumor pathway. We extended these findings to two pathways of programmed myeloid tryptophan metabolism (IDO1, IDO2, IL4i1). Like Arg1, expression of these enzymes was confined to myeloid cells in humans and mice, and each enzyme was independently essential for tumor formation and growth. The protective effects of genetic ablation of each myeloid amino acid pathways uniformly occurred early in tumor formation, arguing that a network of immune cells controlled by myeloid amino acid metabolism and CD4+ T cells is important for the origins of a pro-tumor environment. Our results establish an unappreciated potency of macrophage amino acid metabolism in promoting malignancy, and suggest that these pathways can be disabled by targeting of myeloid amino acid metabolism. OVA-specific CD4+ T cells were stimulated with peptide in the presence of APCs (CD3-depleted splenocytes) either in control complete RPMI-1640 (containing 10% dialyzed FBS) or in RPMI-1640 (containing 10% dialyzed FBS) containing 1% of the normal arginine levels (12uM) to characterize the effects of limited arginine availability on gene expression.
2021-10-13 | GSE126024 | GEO
Project description:Affinity ligands such as antibodies are widely used in (bio)medical research for purifying proteins from complex biological samples. These ligands are generally immobilized onto solid supports which facilitate the separation of captured protein from sample matrix. Adsorptive microtiter plates are commonly used as solid supports prior to immunochemical detection (e.g. immunoassays) but hardly ever prior to LC-MS-based detection, and here we describe some applications, opportunities, and challenges of corresponding workflows.
2021-11-25 | PXD027530 | Pride
Project description:Excitatory amino acid transporter 1 supports adult hippocampal neural stem cell self-renewal.
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Project description:Glutamine is a key nutrient for tumor cells that supports nucleotide and amino acid biosynthesis, replenishes the TCA cycle intermediates and contributes to redox metabolism. We identified oncogenic KRAS as a critical regulator of the response to glutamine deprivation in NSCLC. Full activation of the ATF4 stress response pathway is dependent on expression of NRF2 downstream of oncogenic KRAS in NSCLC. Through this mechanism, KRAS alters amino acid uptake and metabolism and sustains mTORC1 signaling during nutrient stress. Furthermore, we identified regulation of asparagine synthetase (ASNS) as a key effect of oncogenic KRAS signaling via ATF4 during glutamine deprivation, and a potential therapeutic target in KRAS mutant NSCLC.
2017-12-30 | GSE81643 | GEO
Project description:Glutamine is a key nutrient for tumor cells that supports nucleotide and amino acid biosynthesis, replenishes the TCA cycle intermediates and contributes to redox metabolism. We identified oncogenic KRAS as a critical regulator of the response to glutamine deprivation in NSCLC. Full activation of the ATF4 stress response pathway is dependent on expression of NRF2 downstream of oncogenic KRAS in NSCLC. Through this mechanism, KRAS alters amino acid uptake and metabolism and sustains mTORC1 signaling during nutrient stress. Furthermore, we identified regulation of asparagine synthetase (ASNS) as a key effect of oncogenic KRAS signaling via ATF4 during glutamine deprivation, and a potential therapeutic target in KRAS mutant NSCLC.
2017-12-30 | GSE81642 | GEO
Project description:Glutamine is a key nutrient for tumor cells that supports nucleotide and amino acid biosynthesis, replenishes the TCA cycle intermediates and contributes to redox metabolism. We identified oncogenic KRAS as a critical regulator of the response to glutamine deprivation in NSCLC. Full activation of the ATF4 stress response pathway is dependent on expression of NRF2 downstream of oncogenic KRAS in NSCLC. Through this mechanism, KRAS alters amino acid uptake and metabolism and sustains mTORC1 signaling during nutrient stress. Furthermore, we identified regulation of asparagine synthetase (ASNS) as a key effect of oncogenic KRAS signaling via ATF4 during glutamine deprivation, and a potential therapeutic target in KRAS mutant NSCLC.
2017-12-30 | GSE81641 | GEO
Project description:Dynamic partitioning of branched-chain amino acids- derived nitrogen supports renal cancer progression
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Project description:Neandertal Amino Acid Capture project
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Project description:Cyclic 3',5'-adenosine monophosphate (cAMP) phosphodiesterase (CPD) is an enzyme that catalyzes the hydrolysis of cAMP, a signaling molecule affecting diverse cellular and metabolic processes in bacteria. Some CPDs are also known to function in cAMP-independent manners, while their physiological roles remain largely unknown. Here, we investigated physiological roles of CPD in Shewanella oneidensis MR-1, a model environmental bacterium, and report that CPD is involved in amino-acid metabolism. We found that a CPD-deficient mutant of MR-1 (ΔcpdA) showed decreased expression of genes for the synthesis of methionine, S-adenosylmethionine, and histidine and required these three compounds to grow in minimal media. Interestingly, deletion of adenylate cyclases in ΔcpdA did not restore the ability to grow in minimal media, indicating that the amino acid requirements were not due to the accumulation of cAMP. These results suggest that CPD is involved in the regulation of amino acid metabolism in MR-1 in a cAMP-independent manner.
2018-02-21 | GSE97220 | GEO