Cell Reports (Jan 2024)
An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma
- Stephanie M. Casillo,
- Taylor A. Gatesman,
- Akanksha Chilukuri,
- Srinidhi Varadharajan,
- Brenden J. Johnson,
- Daniel R. David Premkumar,
- Esther P. Jane,
- Tritan J. Plute,
- Robert F. Koncar,
- Ann-Catherine J. Stanton,
- Carlos A.O. Biagi-Junior,
- Callie S. Barber,
- Matthew E. Halbert,
- Brian J. Golbourn,
- Katharine Halligan,
- Andrea F. Cruz,
- Neveen M. Mansi,
- Allison Cheney,
- Steven J. Mullett,
- Clinton Van’t Land,
- Jennifer L. Perez,
- Max I. Myers,
- Nishant Agrawal,
- Joshua J. Michel,
- Yue-Fang Chang,
- Olena M. Vaske,
- Antony MichaelRaj,
- Frank S. Lieberman,
- James Felker,
- Sruti Shiva,
- Kelsey C. Bertrand,
- Nduka Amankulor,
- Costas G. Hadjipanayis,
- Kalil G. Abdullah,
- Pascal O. Zinn,
- Robert M. Friedlander,
- Taylor J. Abel,
- Javad Nazarian,
- Sriram Venneti,
- Mariella G. Filbin,
- Stacy L. Gelhaus,
- Stephen C. Mack,
- Ian F. Pollack,
- Sameer Agnihotri
Affiliations
- Stephanie M. Casillo
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Taylor A. Gatesman
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Akanksha Chilukuri
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Srinidhi Varadharajan
- Department 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. Johnson
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Daniel R. David Premkumar
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Esther P. Jane
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Tritan J. Plute
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Robert F. Koncar
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Ann-Catherine J. Stanton
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Carlos A.O. Biagi-Junior
- Department 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. Barber
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Matthew E. Halbert
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Brian J. Golbourn
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Katharine Halligan
- Division 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. Cruz
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Neveen M. Mansi
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Allison Cheney
- Department 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. Mullett
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Clinton Van’t Land
- Division 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. Perez
- Department of Neurological Surgery, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA
- Max I. Myers
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Nishant Agrawal
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Joshua J. Michel
- Rangos Flow Cytometry Core Laboratory, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15224, USA
- Yue-Fang Chang
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Olena M. Vaske
- Department 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 MichaelRaj
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Frank S. Lieberman
- Adult Neuro-Oncology Program, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
- James Felker
- Pediatric Neuro-Oncology Program, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
- Sruti Shiva
- Department 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. Bertrand
- Department 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 Amankulor
- Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA
- Costas G. Hadjipanayis
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Kalil G. Abdullah
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Pascal O. Zinn
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Robert M. Friedlander
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Taylor J. Abel
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Javad Nazarian
- Brain Tumor Institute, Children’s National Hospital, Washington, DC 20010, USA
- Sriram Venneti
- Laboratory 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. Filbin
- Department 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. Gelhaus
- Department 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. Mack
- Department 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. Pollack
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Sameer Agnihotri
- Department 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; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 1
p. 113557
Abstract
Summary: 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.
