bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–10–13
fourteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Histone lactylation drives CD8+ T cell metabolism and function.
  2. Sensing steroid hormone 17α-hydroxypregnenolone by GPR56 enables protection from ferroptosis-induced liver injury.
  3. Maintenance of hematopoietic stem cells by tyrosine-unphosphorylated STAT5 and JAK inhibition.
  4. GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency.
  5. CD38 and the mitochondrial calcium uniporter contribute to age-related hematopoietic stem cell dysfunction.
  6. B-cell Interleukin 1 Receptor 1 (IL1R1) modulates the female adipose tissue immune microenvironment during aging.
  7. Cancer-induced systemic pre-conditioning of distant organs: building a niche for metastatic cells.
  8. Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes.
  9. LPS-induced lung tissue-resident trained innate immunity provides differential protection against pneumococci and SARS-CoV-2.
  10. Inflammation in a ferroptotic environment.
  11. Type I IFN drives unconventional IL-1β secretion in lupus monocytes.
  12. The Protective Role of Transcription Factor Nrf2 in Murine Macrophage Activation Syndrome.
  13. BCKDH kinase promotes hepatic gluconeogenesis independent of BCKDHA.
  14. MYC-dependent upregulation of the de novo serine and glycine synthesis pathway is a targetable metabolic vulnerability in group 3 medulloblastoma.
  1. Nat Immunol. 2024 Oct 07.
    Histone lactylation drives CD8+ T cell metabolism and function.
    Deblina Raychaudhuri, Pratishtha Singh, Bidisha Chakraborty, Mercedes Hennessey, Aminah J Tannir, Shrinidhi Byregowda, Seanu Meena Natarajan, Abel Trujillo-Ocampo, Jin Seon Im, Sangeeta Goswami.
      The activation and functional differentiation of CD8+ T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification; however, the relevance of histone lactylation in the context of CD8+ T cell activation and function is not known. Here, we show the enrichment of H3K18 lactylation (H3K18la) and H3K9 lactylation (H3K9la) in human and mouse CD8+ T cells, which act as transcription initiators of key genes regulating CD8+ T cell function. Further, we note distinct patterns of H3K18la and H3K9la in CD8+ T cell subsets linked to their specific metabolic profiles. Additionally, we find that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways influence CD8+ T cell effector function, including antitumor immunity, in preclinical models. Overall, our study uncovers the potential roles of H3K18la and H3K9la in CD8+ T cells.
    DOI:  https://doi.org/10.1038/s41590-024-01985-9
  2. Cell Metab. 2024 Oct 04. pii: S1550-4131(24)00371-1. [Epub ahead of print]
    Sensing steroid hormone 17α-hydroxypregnenolone by GPR56 enables protection from ferroptosis-induced liver injury.
    Hui Lin, Chuanshun Ma, Xiao Zhuang, Shuo Liu, Dong Liu, Mingxiang Zhang, Yan Lu, Guangjian Zhou, Chao Zhang, Tengwei Wang, Zihao Zhang, Lin Lv, Daolai Zhang, Xiong-Zhong Ruan, Yunfei Xu, Renjie Chai, Xiao Yu, Jin-Peng Sun, Bo Chu.
      G protein-coupled receptors (GPCRs) mediate most cellular responses to hormones, neurotransmitters, and environmental stimulants. However, whether GPCRs participate in tissue homeostasis through ferroptosis remains unclear. Here we identify that GPR56/ADGRG1 renders cells resistant to ferroptosis and deficiency of GPR56 exacerbates ferroptosis-mediated liver injury induced by doxorubicin (DOX) or ischemia-reperfusion (IR). Mechanistically, GPR56 decreases the abundance of phospholipids containing free polyunsaturated fatty acids (PUFAs) by promoting endocytosis-lysosomal degradation of CD36. By screening a panel of steroid hormones, we identified that 17α-hydroxypregnenolone (17-OH PREG) acts as an agonist of GPR56 to antagonize ferroptosis and efficiently attenuates liver injury before or after insult. Moreover, disease-associated GPR56 mutants were unresponsive to 17-OH PREG activation and insufficient to defend against ferroptosis. Together, our findings uncover that 17-OH PREG-GPR56 axis-mediated signal transduction works as a new anti-ferroptotic pathway to maintain liver homeostasis, providing novel insights into the potential therapy for liver injury.
    Keywords:  17α-hydroxypregnenolone; GPR56; ferroptosis; liver injury
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.007
  3. Blood Adv. 2024 Oct 07. pii: bloodadvances.2024014046. [Epub ahead of print]
    Maintenance of hematopoietic stem cells by tyrosine-unphosphorylated STAT5 and JAK inhibition.
    Matthew J Williams, Xiaonan Wang, Hugo P Bastos, Gabriela Grondys-Kotarba, Qin Wu, Shucheng Jin, Carys S Johnson, Nicole Mende, Emily Francesca Calderbank, Michelle Wantoch, Hyun Jung Park, Giovanna Mantica, Rebecca Louise Hannah, Nicola K Wilson, Dean C Pask, Tina L Hamilton, Sarah J Kinston, Ryan Asby, Rachel Sneade, E Joanna Baxter, Peter J Campbell, George S Vassiliou, Elisa Laurenti, Juan Li, Berthold Gottgens, Anthony R Green.
      Adult haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood and immune cells, a process regulated by extracellular cues including cytokines. Many cytokines signal through the conserved JAK/STAT pathway, in which tyrosine-phosphorylated STATs (pSTATs) function as transcription factors. STAT5 is a pivotal downstream mediator of several cytokines known to regulate haematopoiesis but its function in the HSC compartment remains poorly understood. Here, we show that STAT5-deficient HSCs exhibit an unusual phenotype: reduced multi-lineage repopulation and self-renewal, combined with reduced exit from quiescence and increased differentiation. This was driven not only by loss of canonical pSTAT5 signalling, but also by loss of distinct transcriptional functions mediated by STAT5 lacking canonical tyrosine phosphorylation (uSTAT5). Consistent with this concept, expression of an unphosphorylatable STAT5 mutant constrained wild-type HSC differentiation, promoted their maintenance and upregulated transcriptional programs associated with quiescence and stemness. The JAK1/2 inhibitor, ruxolitinib, which increased the uSTAT5:pSTAT5 ratio, had similar effects on murine HSC function: it constrained HSC differentiation and proliferation, promoted HSC maintenance and upregulated transcriptional programs associated with stemness. Ruxolitinib also enhanced serial replating of normal human HSPCs, CALR-mutant murine HSCs and HSPCs obtained from patients with myelofibrosis. Our results therefore reveal a previously unrecognized interplay between pSTAT5 and uSTAT5 in the control of HSC function and highlight JAK inhibition as a potential strategy for enhancing HSC function during ex vivo culture. Increased levels of uSTAT5 may also contribute to the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014046
  4. Nat Commun. 2024 Oct 06. 15(1): 8658
    GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency.
    Justin A Guerrero, Dorota D Klysz, Yiyun Chen, Meena Malipatlolla, Jameel Lone, Carley Fowler, Lucille Stuani, Audre May, Malek Bashti, Peng Xu, Jing Huang, Basil Michael, Kévin Contrepois, Shaurya Dhingra, Chris Fisher, Katrin J Svensson, Kara L Davis, Maya Kasowski, Steven A Feldman, Elena Sotillo, Crystal L Mackall.
      The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function.
    DOI:  https://doi.org/10.1038/s41467-024-52666-y
  5. Immunometabolism (Cobham). 2024 Oct;6(4): e00048
    CD38 and the mitochondrial calcium uniporter contribute to age-related hematopoietic stem cell dysfunction.
    Connor S R Jankowski, Thomas Weichhart.
      Hematopoietic stem cells (HSCs) are the multipotent progenitors of all immune cells. During aging, their regenerative capacity decreases for reasons that are not well understood. Recently, Song et al investigated the roles of two metabolic proteins in age-related HSC dysfunction: CD38 (a membrane-bound NADase) and the mitochondrial calcium uniporter that transports calcium into the mitochondrial matrix. They found that the interplay between these proteins is deranged in aged HSCs, contributing to their diminished renewal capacity. These findings implicate compromised nicotinamide adenine dinucleotide metabolism as underlying HSC dysfunction in aging.
    Keywords:  CD38; aging; hematopoiesis; mitochondria; mitochondrial calcium uniporter; nicotinamide adenine dinucleotide metabolism
    DOI:  https://doi.org/10.1097/IN9.0000000000000048
  6. J Leukoc Biol. 2024 Oct 08. pii: qiae219. [Epub ahead of print]
    B-cell Interleukin 1 Receptor 1 (IL1R1) modulates the female adipose tissue immune microenvironment during aging.
    Anna Carey, Louise E Pitcher, In Hwa Jang, Katie Nguyen, Stephanie Cholensky, Paul D Robbins, Christina D Camell.
      Myeloid cell production of interleukin-1β (IL-1β) drives inflammaging in visceral adipose tissue (vWAT) and contributes to the expansion of interleukin-1 receptor 1 (Il1r1) positive aged adipose B-cells (AABs). AABs promote metabolic dysfunction and inflammation under inflammatory challenges. However, it is unclear whether IL-1β contributes to AAB-associated inflammation during aging. Using a B-cell specific knockout of Il1r1 (BKO mice), we characterized old vWAT in the absence of IL-1β - B-cell signaling. In addition to sex-specific metabolic improvements in females, we identified a reduction in the proportion of B-cells and a sex-specific increase in the B1:B2 B-cell ratio in BKO vWAT. Using single cell RNA-sequencing of vWAT immune cells, we observed that BKO differentially affected inflammatory signaling in vWAT immune cells. These data suggest that IL-1β - B-cell signaling supports the inflammatory response in multiple cell types and provides insight into the complex microenvironment in aged vWAT.
    Keywords:  B-cells; IL-1β signaling; adipose tissue; aging; macrophages
    DOI:  https://doi.org/10.1093/jleuko/qiae219
  7. Nat Rev Cancer. 2024 Oct 10.
    Cancer-induced systemic pre-conditioning of distant organs: building a niche for metastatic cells.
    Nicolas Rabas, Rute M M Ferreira, Stefania Di Blasio, Ilaria Malanchi.
      From their early genesis, tumour cells integrate with the surrounding normal cells to form an abnormal structure that is tightly integrated with the host organism via blood and lymphatic vessels and even neural associations. Using these connections, emerging cancers send a plethora of mediators that efficiently perturb the entire organism and induce changes in distant tissues. These perturbations serendipitously favour early metastatic establishment by promoting a more favourable tissue environment (niche) that supports the persistence of disseminated tumour cells within a foreign tissue. Because the establishment of early metastatic niches represents a key limiting step for metastasis, the creation of a more suitable pre-conditioned tissue strongly enhances metastatic success. In this Review, we provide an updated view of the mechanisms and mediators of primary tumours described so far that induce a pro-metastatic conditioning of distant organs, which favours early metastatic niche formation. We reflect on the nature of cancer-induced systemic conditioning, considering that non-cancer-dependent perturbations of tissue homeostasis are also able to trigger pro-metastatic conditioning. We argue that a more holistic view of the processes catalysing metastatic progression is needed to identify preventive or therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41568-024-00752-0
  8. Sci Transl Med. 2024 Oct 09. 16(768): eado3022
    Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes.
    David Rizo-Roca, Dimitrius Santiago P S F Guimarães, Logan A Pendergrast, Nicolas Di Leo, Alexander V Chibalin, Salwan Maqdasy, Mikael Rydén, Erik Näslund, Juleen R Zierath, Anna Krook.
      Increased plasma creatine concentrations are associated with the risk of type 2 diabetes, but whether this alteration is associated with or causal for impairments in metabolism remains unexplored. Because skeletal muscle is the main disposal site of both creatine and glucose, we investigated the role of intramuscular creatine metabolism in the pathophysiology of insulin resistance in type 2 diabetes. In men with type 2 diabetes, plasma creatine concentrations were increased, and intramuscular phosphocreatine content was reduced. These alterations were coupled to reduced expression of sarcomeric mitochondrial creatine kinase 2 (CKMT2). In C57BL/6 mice fed a high-fat diet, neither supplementation with creatine for 2 weeks nor treatment with the creatine analog β-GPA for 1 week induced changes in glucose tolerance, suggesting that increased circulating creatine was associated with insulin resistance rather than causing it. In C2C12 myotubes, silencing Ckmt2 using small interfering RNA reduced mitochondrial respiration, membrane potential, and glucose oxidation. Electroporation-mediated overexpression of Ckmt2 in skeletal muscle of high-fat diet-fed male mice increased mitochondrial respiration, independent of creatine availability. Given that overexpression of Ckmt2 improved mitochondrial function, we explored whether exercise regulates CKMT2 expression. Analysis of public data revealed that CKMT2 content was up-regulated by exercise training in both humans and mice. We reveal a previously underappreciated role of CKMT2 in mitochondrial homeostasis beyond its function for creatine phosphorylation, independent of insulin action. Collectively, our data provide functional evidence for how CKMT2 mediates mitochondrial dysfunction associated with type 2 diabetes.
    DOI:  https://doi.org/10.1126/scitranslmed.ado3022
  9. Cell Rep. 2024 Oct 08. pii: S2211-1247(24)01200-2. [Epub ahead of print]43(10): 114849
    LPS-induced lung tissue-resident trained innate immunity provides differential protection against pneumococci and SARS-CoV-2.
    Alisha Kang, Gluke Ye, Sam Afkhami, Fatemah Aleithan, Kanwaldeep Singh, Anna Dvorkin-Gheva, Tobias Berg, Matthew S Miller, Mangalakumari Jeyanathan, Zhou Xing.
      Recent evidence indicates that tissue-resident innate immune memory and trained innate immunity (TII) can be induced centrally in myeloid cells within the bone marrow and locally in tissue-resident macrophages in respiratory mucosal tissues. However, it remains unclear whether acute exposure to airborne microbial components like lipopolysaccharide (LPS) induces lasting innate immune memory in airway macrophages and TII capable of protection against heterologous pathogens. Using a murine model, we demonstrate that acute LPS exposure leads to dynamic changes in the immune phenotype of airway macrophages that persist long after the acute inflammatory response has subsided. The original airway-resident alveolar macrophage pool remains stable in size despite these changes and the earlier transient acute inflammatory responses, including monocytic recruitment in the lung. We further demonstrate that the induction of innate immune memory in airway macrophages is accompanied by TII capable of robust protection against acute pneumococcal infection, whereas it provides minimal protection against acute SARS-CoV-2 infection.
    Keywords:  CP: Immunology
    DOI:  https://doi.org/10.1016/j.celrep.2024.114849
  10. Front Pharmacol. 2024 ;15 1474285
    Inflammation in a ferroptotic environment.
    Anja Wickert, Anna Schwantes, Dominik C Fuhrmann, Bernhard Brüne.
      Ferroptosis is an iron-dependent form of cell death, which finally culminates in lipid peroxidation and membrane damage. During the past decade, the interest in ferroptosis increased substantially and various regulatory components were discovered. The role of ferroptosis during inflammation and its impact on different immune cell populations is still under debate. Activation of inflammatory pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and hypoxia inducible factors (HIFs) are known to alter the ability of cells to undergo ferroptosis and are closely connected to iron metabolism. During inflammation, iron regulatory systems fundamentally change and cells such as macrophages and neutrophils adapt their metabolism towards iron sequestering phenotypes. In this review, we discuss how ferroptosis alters inflammatory pathways and how iron metabolism under inflammatory conditions affects immune cell ferroptosis.
    Keywords:  HIF; LCN2; NF-kB; iron; lipid peroxidation
    DOI:  https://doi.org/10.3389/fphar.2024.1474285
  11. Immunity. 2024 Oct 03. pii: S1074-7613(24)00448-5. [Epub ahead of print]
    Type I IFN drives unconventional IL-1β secretion in lupus monocytes.
    Simone Caielli, Preetha Balasubramanian, Juan Rodriguez-Alcazar, Uthra Balaji, Lauren Robinson, Zurong Wan, Jeanine Baisch, Cynthia Smitherman, Lynnette Walters, Paola Sparagana, Djamel Nehar-Belaid, Radu Marches, Lorien Nassi, Katie Stewart, Julie Fuller, Jacques F Banchereau, Jinghua Gu, Tracey Wright, Virginia Pascual.
      Opsonization of red blood cells that retain mitochondria (Mito+ RBCs), a feature of systemic lupus erythematosus (SLE), triggers type I interferon (IFN) production in macrophages. We report that monocytes (Mos) co-produce IFN and mature interleukin-1β (mIL-1β) upon Mito+ RBC opsonization. IFN expression depended on cyclic GMP-AMP synthase (cGAS) and RIG-I-like receptors' (RLRs) sensing of Mito+ RBC-derived mitochondrial DNA (mtDNA) and mtRNA, respectively. Interleukin-1β (IL-1β) production was initiated by the RLR antiviral signaling adaptor (MAVS) pathway recognition of Mito+ RBC-derived mtRNA. This led to the cytosolic release of Mo mtDNA, which activated the inflammasome. Importantly, mIL-1β secretion was independent of gasdermin D (GSDMD) and pyroptosis but relied on IFN-inducible myxovirus-resistant protein 1 (MxA), which facilitated the incorporation of mIL-1β into a trans-Golgi network (TGN)-mediated secretory pathway. RBC internalization identified a subset of blood Mo expressing IFN-stimulated genes (ISGs) that released mIL-1β and expanded in SLE patients with active disease.
    Keywords:  MxA; NLRP3; inflammasome; monocytes; red blood cells; systemic lupus erythematosus; type I interferon
    DOI:  https://doi.org/10.1016/j.immuni.2024.09.004
  12. J Leukoc Biol. 2024 Oct 11. pii: qiae225. [Epub ahead of print]
    The Protective Role of Transcription Factor Nrf2 in Murine Macrophage Activation Syndrome.
    Paul M Gallo, Em Elliott, Grace C Ford, Chhanda Biswas, Jadyn M Wheaton, Jihwan Kim, Connie L Jiang, Niansheng Chu, Portia A Kreiger, Michele P Lambert, Edward M Behrens.
       OBJECTIVE: Macrophage activation syndrome (MAS) is characterized by multi-lineage cytopenias, hypercytokinemia, and tissue hemophagocytosis. Transcription factor Nrf2 is a master regulator of redox homeostasis. In this work we aim to investigate the role of Nrf2 in murine hyperinflammation and the mechanisms by which Nrf2 activation by red blood cell products regulates pro-inflammatory cytokine production.
    METHODS: We induce murine MAS in wildtype and Nrf2 knockout (Nrf2 -/-) mice by repeat administration of TLR9-agonist CpG. Clinical and biochemical markers of disease were measured including complete blood counts, liver and spleen pathology, serum free heme, ferritin, and cytokine profiles. In vitro bone marrow derived macrophages and dendritic cells were used to investigate regulation of CpG-induced cytokine expression by oxidized red blood cells and hemin.
    RESULTS: Patients with hyperinflammatory disease have higher levels of Nrf2 gene expression. Mice with CpG-induced hyperinflammation have elevated systemic lipid peroxidation which is exacerbated in Nrf2 -/- mice. Compared to wildtype controls, Nrf2 -/- mice develop significantly worse organomegaly, organ pathology, and reticulocytosis. Nrf2 -/- mice have exacerbated hypercytokinemia in cytokines central MAS physiology: IL-12, IFNg, and IL-10. In vitro we found that oxidized red blood cell lysates and hemin are able to suppress IL-12 transcription and protein production from bone marrow derived dendritic cells in a Nrf2-dependent manner.
    CONCLUSION: Together our findings show that transcription factor Nrf2 is highly expressed in patients with hyperinflammatory disease and demonstrate a protective role for Nrf2 in a murine model of MAS in part due to Nrf2-mediated suppression of proinflammatory cytokine production.
    Keywords:  Hemophagocytosis; Inflammation; Macrophage activation syndrome
    DOI:  https://doi.org/10.1093/jleuko/qiae225
  13. Cell Death Dis. 2024 Oct 10. 15(10): 736
    BCKDH kinase promotes hepatic gluconeogenesis independent of BCKDHA.
    Feiye Zhou, Chunxiang Sheng, Xiaoqin Ma, Tianjiao Li, Xing Ming, Shushu Wang, Jialin Tan, Yulin Yang, Haipeng Sun, Jieli Lu, Jianmin Liu, Ruyuan Deng, Xiao Wang, Libin Zhou.
      Elevated circulating branched-chain amino acids (BCAAs) are tightly linked to an increased risk in the development of type 2 diabetes mellitus. The rate limiting enzyme of BCAA catabolism branched-chain α-ketoacid dehydrogenase (BCKDH) is phosphorylated at E1α subunit (BCKDHA) by its kinase (BCKDK) and inactivated. Here, the liver-specific BCKDK or BCKDHA knockout mice displayed normal glucose tolerance and insulin sensitivity. However, knockout of BCKDK in the liver inhibited hepatic glucose production as well as the expression of key gluconeogenic enzymes. No abnormal gluconeogenesis was found in mice lacking hepatic BCKDHA. Consistent with the vivo results, BT2-mediated inhibition or genetic knockdown of BCKDK decreased hepatic glucose production and gluconeogenic gene expressions in primary mouse hepatocytes while BCKDK overexpression exhibited an opposite effect. Whereas, gluconeogenic gene expressions were not altered in BCKDHA-silenced hepatocytes. Mechanistically, BT2 treatment attenuated the interaction of cAMP response element binding protein (CREB) with CREB-binding protein and promoted FOXO1 protein degradation by increasing its ubiquitination. Our findings suggest that BCKDK regulates hepatic gluconeogenesis through CREB and FOXO1 signalings, independent of BCKDHA-mediated BCAA catabolism.
    DOI:  https://doi.org/10.1038/s41419-024-07071-0
  14. Neuro Oncol. 2024 Oct 08. pii: noae179. [Epub ahead of print]
    MYC-dependent upregulation of the de novo serine and glycine synthesis pathway is a targetable metabolic vulnerability in group 3 medulloblastoma.
    Magretta Adiamah, Bethany Poole, Janet C Lindsey, Sarah Kohe, Alaide Morcavallo, Florence Burté, Rebecca M Hill, Helen Blair, Dean Thompson, Mankaran Singh, Shanel Swartz, Stephen Crosier, Tong Zhang, Oliver D K Maddocks, Andrew Peet, Louis Chesler, Ian Hickson, Ross J Maxwell, Steven C Clifford.
       BACKGROUND: Group 3 medulloblastoma (MBGRP3) represents around 25% of medulloblastomas and is strongly associated with c-MYC (MYC) amplification, which confers significantly worse patient survival. Although elevated MYC expression is a significant molecular feature in MBGRP3, direct targeting of MYC remains elusive, and alternative strategies are needed. The metabolic landscape of MYC-driven MBGRP3 is largely unexplored and may offer novel opportunities for therapies.
    METHODS: To study MYC-induced metabolic alterations in MBGRP3, we depleted MYC in isogenic cell-based model systems, followed by 1H high-resolution magic-angle spectroscopy (HRMAS) and stable isotope-resolved metabolomics, to assess changes in intracellular metabolites and pathway dynamics.
    RESULTS: Steady-state metabolic profiling revealed consistent MYC-dependent alterations in metabolites involved in one-carbon metabolism such as glycine. 13C-glucose tracing further revealed a reduction in glucose-derived serine and glycine (de novo synthesis) following MYC knockdown, which coincided with lower expression and activity of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in this pathway. Furthermore, MYC-overexpressing MBGRP3 cells were more vulnerable to pharmacological inhibition of PHGDH compared to those with low expression. Using in vivo tumor-bearing genetically engineered and xenograft mouse models, pharmacological inhibition of PHGDH increased survival, implicating the de novo serine/glycine synthesis pathway as a pro-survival mechanism sustaining tumor progression. Critically, in primary human medulloblastomas, increased PHGDH expression correlated strongly with both MYC amplification and poorer clinical outcomes.
    CONCLUSIONS: Our findings support a MYC-induced dependency on the serine/glycine pathway in MBGRP3 that represents a novel therapeutic treatment strategy for this poor prognosis disease group.
    Keywords:  MYC; PHGDH; medulloblastoma; metabolism; serine
    DOI:  https://doi.org/10.1093/neuonc/noae179
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