Inverse data-driven modelling and multiomics analysis reveals PHGDH as a metabolic signature of M2 macrophages
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE118119 | GEO | 2019/08/04
REPOSITORIES: GEO
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Project description:Activation of immune cells is accompanied by a metabolic reconfiguration of their cellular energy metabolism including shifts in glycolysis and mitochondrial respiration that critically regulate functional effector responses. However, while current mass spectrometry strategies identify overall or flux-dependent metabolite profiles of cells or tissues, they fail to comprehensively identify the checkpoint nodes and enzymes that are responsible for different metabolic outputs. Here, we demonstrate that a data-driven inverse modelling approach from mass spectrometry metabolomics data can be used to identify a causal biochemical node that influence overall metabolic profiles and reactions. In our study we applied this strategy to TSC2/mTORC1-dependent macrophage polarization. Using multiomics metabolomics, proteomics and transcriptomics analysis as well as enzymatic activity measurements we demonstrate that TSC2, a negative regulator of mTORC1 signaling, critically influences the cellular metabolism of macrophages by regulating the enzyme phosphoglycerate dehydrogenase (PHGDH), a rate-limiting enzyme that diverts carbon from glycolysis for de novo serine/glycine biosynthesis. This is the first evidence that the metabolic kinase mTORC1 positively regulates PHGDH activity in macrophages. Importantly, PHGDH itself is a central regulator of macrophage polarization. Anti-inflammatory (M2) macrophages have high PHGDH activity that is required for the expression of typical anti-inflammatory molecules. Inhibition of PHGDH activity suppressed marker genes in IL-4 stimulated M2 macrophages. This identifies PHGDH as a metabolic signature of M2 macrophages. The presented concept of data-driven inverse modelling and multiomics analysis allows for the systematic integration of genome-scale metabolic reconstruction, prediction and analysis of causal biochemical regulation.
2020-05-26 | PXD010657 | Pride
Project description:Inverse data-driven modelling and multiomics analysis reveals PHGDH as a metabolic signature of M2 macrophages
| PRJNA484506 | ENA
Project description:Mechanistic or mammalian target of rapamycin complex 1 (mTORC1) is an important regulator of effector functions, proliferation, and cellular metabolism in macrophages. The biochemical processes that are controlled by mTORC1 are still being defined. Here, we demonstrate that integrative multiomics in conjunction with a data-driven inverse modeling approach, termed COVRECON, identifies a biochemical node that influences overall metabolic profiles and reactions of mTORC1-dependent macrophage metabolism. Using a combined approach of metabolomics, proteomics, mRNA expression analysis, and enzymatic activity measurements, we demonstrate that Tsc2, a negative regulator of mTORC1 signaling, critically influences the cellular activity of macrophages by regulating the enzyme phosphoglycerate dehydrogenase (Phgdh) in an mTORC1-dependent manner. More generally, while lipopolysaccharide (LPS)-stimulated macrophages repress Phgdh activity, IL-4-stimulated macrophages increase the activity of the enzyme required for the expression of key anti-inflammatory molecules and macrophage proliferation. Thus, we identify Phgdh as a metabolic checkpoint of M2 macrophages.
| S-EPMC7003064 | biostudies-literature
Project description:D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is a necessary enzyme for de novo L-serine biosynthesis via the phosphorylated pathway. We demonstrated previously that Phgdh is expressed exclusively by neuroepithelium and radial glia in developing mouse brain and later mainly by astrocytes. Mutations in the human PHGDH gene cause serine deficiency disorders (SDD) associated with severe neurological symptoms such as congenital microcephaly, psychomotor retardation, and intractable seizures. We recently demonstrated that genetically engineered mice, in which the gene for Phgdh has been disrupted, have significantly decreased levels of serine and glycine, and exhibit malformation of brain such as microcephaly. The Phgdh null (KO) embryos exhibit lethal phenotype after gestational day 14, indicating that the phosphorylated pathway is essential for embryogenesis, especially for brain development. It is worth noting that the Phgdh knockout (KO) embryos primarily displayed microcephaly, which is the most conspicuous phenotype of patients with SDD. Thus, Phgdh KO mice are a useful animal model for studying the effect of diminished L-serine levels on development of the central nervous system and other organs. To better understand the mechanism underlying the molecular pathogenesis of SDD, we sought to examine whether gene expression is altered in the Phgdh KO mouse model. We identify genes that have altered expression in the head of the Phgdh KO embryos using the GeneChip array. Some of the genes identified by this method belong in functional categories that are relevant to the biochemical and morphological aberrations of the Phgdh deletion. Experiment Overall Design: Total RNA samples were prepared from head tissues from 2 embryos of Phgdh knockout and littermate wild-type controls. Experiment Overall Design: RNA of 4 biological replicates was hybridized to Affymetrix Mouse Genome 430 2.0 arrays. Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.
2008-06-17 | E-GEOD-8555 | biostudies-arrayexpress
Project description:Metabolic dysregulation is an important feature of malignant tumors. Serine synthesis pathway (SSP) reshapes tumor cells to enhance their growth and survival capabilities, especially under serine starvation. However, whether and how SSP is involved in the progression of liver cancer has not been clearly stated. We applied a combination of quantitative proteomics and transcriptomics and discovered the increased expression of PHGDH and PSAT1 in mice liver cancer induced by SB. PHGDH is the first rating-limited enzyme of SSP and the conditional knockout of PHGDH in liver impaired the advanced liver cancer formation. However, the specific inhibition of enzymatic activity of PHGDH in liver has no obvious suppressive effect on advanced liver cancer. Further, we explored a non-metabolic function of PHGDH, which used its ACT domain to bind and regulate cMyc transcriptional activity, then selectively activated genes expression of Lcn2, Got1, Fabp5 and Psat1, indicating PHGDH drives/links multiple metabolic pathways and augmented its function through its non-metabolic role. In addition, the mutant p53 would release the suppression of PHGDH in mice liver cancer model and clinical liver cancer samples. Hence, the mutant p53/PHGDH/cMyc axis could be a potential target to cure advanced liver cancer.
2023-07-20 | PXD017809 | Pride
Project description:Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process. Metabolic heterogeneity has also been observed, yet its role for cancer progression is less explored. Here, we discover that loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumors of breast cancer patients is associated with decreased metastasis free survival time. In mice, circulating tumor cells and early metastatic lesions are enriched with PHGDH low cancer cells and silencing PHGDH in primary tumors increases metastasis formation. Mechanistically, PHGDH protein interacts with the glycolytic enzyme phosphofructokinase (PFK) and the loss of this interaction activates the hexosamine – sialic acid pathway, which provides precursors for protein glycosylation. Consequently, aberrant protein glycosylation including increased sialylation of integrin αvβ3 occurs, which potentiates cell migration and invasion. Inhibition of sialic acid metabolism counteracts the metastatic capacity of PHGDH low cancer cells. In conclusion, while the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Thus, the presence of PHDGH heterogeneity in primary tumors may be considered a sign of tumor aggressiveness.
2022-03-30 | GSE198380 | GEO
Project description:D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is a necessary enzyme for de novo L-serine biosynthesis via the phosphorylated pathway. We demonstrated previously that Phgdh is expressed exclusively by neuroepithelium and radial glia in developing mouse brain and later mainly by astrocytes. Mutations in the human PHGDH gene cause serine deficiency disorders (SDD) associated with severe neurological symptoms such as congenital microcephaly, psychomotor retardation, and intractable seizures. We recently demonstrated that genetically engineered mice, in which the gene for Phgdh has been disrupted, have significantly decreased levels of serine and glycine, and exhibit malformation of brain such as microcephaly. The Phgdh null (KO) embryos exhibit lethal phenotype after gestational day 14, indicating that the phosphorylated pathway is essential for embryogenesis, especially for brain development. It is worth noting that the Phgdh knockout (KO) embryos primarily displayed microcephaly, which is the most conspicuous phenotype of patients with SDD. Thus, Phgdh KO mice are a useful animal model for studying the effect of diminished L-serine levels on development of the central nervous system and other organs. To better understand the mechanism underlying the molecular pathogenesis of SDD, we sought to examine whether gene expression is altered in the Phgdh KO mouse model. We identify genes that have altered expression in the head of the Phgdh KO embryos using the GeneChip array. Some of the genes identified by this method belong in functional categories that are relevant to the biochemical and morphological aberrations of the Phgdh deletion. Keywords: genetic modification
2007-07-25 | GSE8555 | GEO
Project description:Here we show under glucose deficiency PHGDH is phosphorylated by p38 at Ser371, which promotes the cytosol-localized PHGDH translocation into the nucleus. Meanwhile, AMPK concurrently phosphorylates PHGDH-Ser55 and selectively increases PHGDH catalytic activity against malate oxidation, thus pushing the reduction of NAD+ towards NADH generation. In the nucleus, the altered PHGDH activity positively regulates NADH/NAD+ ratio and thus restricts NAD+ level, and thereby leads to repression of NAD+-dependent PARP1 activity. Moreover, PHGDH is found to be associated with Ser73-phosphorylated c-Jun and specifically inhibits PARP1-mediated c-Jun poly(ADP-ribosyl)ation, which accordingly led to the impaired c-Jun transcriptional activity against genes expression linking to cell growth inhibition.
2021-07-29 | GSE180640 | GEO
Project description:Here we sought metabolic alterations specifically associated with amplified MYCN as nodes to indirectly target the MYCN oncogene. Liquid chromatography-mass spectrometry-based proteomics identified 7 proteins consistently correlated with MYCN in proteomes from 49 neuroblastoma biopsies and 13 cell lines. Among these were phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine synthesis. MYCN associated with two regions in the PHGDH promoter, supporting transcriptional PHGDH regulation by MYCN. Pulsed stable isotope-resolved metabolomics utilizing 13C-glucose labeling demonstrated higher de novo serine synthesis in MYCN-amplified cells compared to cells with diploid MYCN. An independence of MYCN-amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploid MYCN but did not diminish these endpoints in MYCN-amplified cells. Proliferation was attenuated in MYCN-amplified cells by CRISPR/Cas9-mediated PHGDH knockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single-agent therapy to NMRI-Foxn1nu/nu mice harboring patient-derived MYCN-amplified neuroblastoma xenografts slowed tumor growth. However, combining a PHGDH inhibitor with the standard-of-care chemotherapy drug, cisplatin, revealed antagonism of chemotherapy efficacy in vivo. Emergence of chemotherapy resistance was confirmed in the genetic PHGDH knockout model in vitro. Altogether, PHDGH knockout and inhibition by small molecules consistently slows proliferation, but stops short of killing the cells, which then establish resistance to classical chemotherapy. Although PHGDH inhibition with small molecules has produced encouraging results in other preclinical cancer models, this approach must be considered with caution in patients with neuroblastoma.
2020-12-11 | PXD018300 | Pride
Project description:Phosphoglycerate dehydrogenase (PHGDH) has emerged as a crucial factor in facilitating macromolecule synthesis, neutralizing oxidative stress, and regulating methylation reactions in cancer cells, lymphocytes, and endothelial cells. However, the role of PHGDH in tumor-associated macrophages (TAMs) remains poorly understood. Here, we find that T helper 2 (Th2) cytokine interleukin-4 and the tumor-conditioned media increase the expression of PHGDH in macrophages and promote immunosuppressive M2 activation and proliferation. Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration essential for immunosuppressive macrophages. Mechanistically, PHGDH-mediated serine biosynthesis promotes α-ketoglutarate production, which activates mTORC1 signaling and contributes to the maintenance of a M2-like macrophage phenotype in the tumor microenvironment. Genetically ablating PHGDH in macrophages of tumor-bearing mice results in attenuated tumor growth, reduced TAM infiltration, a phenotypic shift of M2-like TAMs towards an M1-like phenotype and enhanced anti-tumor T cell immunity. Our study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.
2024-01-27 | GSE236357 | GEO