Targeting PHGDH reverses the immunosuppressive function in macrophages and enhances cancer immunotherapy
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PROVIDER: PRJNA990696 | ENA |
REPOSITORIES: ENA
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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
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:Metronomic Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy
| PRJNA704676 | ENA
Project description:Metronomic Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy
| PRJNA700409 | ENA
Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.
2015-11-21 | E-GEOD-75233 | biostudies-arrayexpress
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:Intracellular expression of a chimeric antigen reverses resistance to cancer immunotherapy
| PRJNA1029646 | ENA
Project description:Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy
| PRJNA695240 | ENA
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