ArticleCell reports2024
An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.
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Article in Cell reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9citing papers in PubMed
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9 citing papers in PubMed, 15 citations in OpenAlex.
- The evolving landscape of the Warburg effect in gastric cancer: From molecular mechanisms to targeted therapy.Clinical and translational medicine · 2026Review
- Review
- Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in preclinical models of H3K27M-mutant gliomas.Science translational medicine · 2026Article
- VCAN Is Essential for ERK5-Driven Tumorigenesis in Soft Tissue Sarcoma.International journal of biological sciences · 2026Article
- Inhibition of PFKFB3 in Macrophages Has a Dual Effect on Tumor-Regulating Lipid Metabolism.International journal of molecular sciences · 2025Article
- An intermediate activation state primes Langerhans cell migration from the epidermis.bioRxiv : the preprint server for biology · 2025Article
- Consistently processed RNA sequencing data from 50 sources enriched for pediatric data.Scientific data · 2025Article
- Aberrant histone modifications in pediatric brain tumors.Frontiers in oncology · 2025Review
- Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma.Nature communications · 2024Article
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Authors and funding
44 authors at 9 institutions in 1 country.
Stephanie M CasilloDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Taylor A GatesmanDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Akanksha ChilukuriDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Srinidhi VaradharajanDepartment of Pediatric Hematology and Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Brenden J JohnsonDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Daniel R David PremkumarDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Esther P JaneDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Tritan J PluteDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Robert F KoncarDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Ann-Catherine J StantonDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Carlos A O Biagi-JuniorDepartment of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Callie S BarberDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Matthew E HalbertDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Brian J GolbournDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Katharine HalliganDivision of Hematology Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pittsburgh, PA 15261, USA; Division of Hematology Oncology, Department of Pediatrics, Albany Medical College, Albany, NY 12208, USA.
Andrea F CruzDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Neveen M MansiDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Allison CheneyDepartment of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; University of California, Santa Cruz Genomics Institute, Santa Cruz, CA 95064, USA.
Steven J MullettDepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Clinton Van't LandDivision of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Rangos Metabolic Core Facility, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15224, USA.
Jennifer L PerezDepartment of Neurological Surgery, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA.
Max I MyersDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Nishant AgrawalDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Joshua J MichelRangos Flow Cytometry Core Laboratory, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15224, USA.
Yue-Fang ChangDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Olena M VaskeDepartment of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; University of California, Santa Cruz Genomics Institute, Santa Cruz, CA 95064, USA.
Antony MichaelRajDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Frank S LiebermanAdult Neuro-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
James FelkerPediatric Neuro-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
Sruti ShivaDepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Heart, Lung, Blood, and Vascular Medicine Institute, Department of Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Kelsey C BertrandDepartment of Pediatric Hematology and Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Nduka AmankulorDepartment of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
Costas G HadjipanayisDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Kalil G AbdullahDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Pascal O ZinnDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Robert M FriedlanderDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Taylor J AbelDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Javad NazarianBrain Tumor Institute, Children's National Hospital, Washington, DC 20010, USA.
Sriram VennetiLaboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Mariella G FilbinDepartment of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Stacy L GelhausDepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA 15224, USA.
Stephen C MackDepartment of Pediatric Hematology and Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Ian F PollackDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Sameer AgnihotriDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Pediatric Neuro-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA. Electronic address: sameer.agnihotri@pitt.edu.
University of Pittsburgh · USSt. Jude Children's Research Hospital · USBroad Institute · USChildren's Hospital of Pittsburgh · USUniversity of California, Santa Cruz · USChildren's National · USMayo Clinic · USUniversity of Michigan · USUniversity of Pennsylvania · US
Funding
Training Program in Molecular, Cell, and Developmental BiologyT32GM133391 · NIGMS · UNIVERSITY OF CALIFORNIA SANTA CRUZ · PI Needhi Bhalla · 2019 to 2026
$3.0MMetabolic Regulation of Glioblastoma EpitranscriptomicsR01CA268634 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Sameer Agnihotri, JEREMY N RICH · 2022 to 2026
$2.9MTargeting extracellular signaling-regulated kinase 5 (ERK5) in brain tumors and their microenvironmentR01NS115831 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI AGNIHOTRI, SAMEER · 2020 to 2024
$1.8MAn Exploris 240 for MetabolomicsS10OD032141 · OD · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GELHAUS, STACY LYNN · 2022 to 2022
$600kBringing Untargeted Metabolomics to PittS10OD023402 · OD · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GELHAUS, STACY LYNN · 2018 to 2018
$594kNCI NIH HHS R01 CA268634NIGMS NIH HHS T32 GM133391NIH HHS S10 OD023402NIH HHS S10 OD032141NINDS NIH HHS R01 NS115831
Abstract
Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.
Indexed as
GliomaHistonesAnimalsChildExtracellular Signal-Regulated MAP KinasesGlycolysisHumansMiceMitogen-Activated Protein Kinase 7Phosphofructokinase-2Phosphoric Monoester HydrolasesSignal TransductionExtracellular Signal-Regulated MAP KinasesHistonesMAPK7 protein, humanMitogen-Activated Protein Kinase 7PFKFB3 protein, humanPhosphofructokinase-2Phosphoric Monoester HydrolasesCP: CancerCP: MetabolismERK5gliomaglycolysisH3K27a-DMGMEF2Ametabolismmulti targetedpediatricPFKFB3synergy
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.