2. Academic Validation
  3. Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma

Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma

  • Mol Cell. 2022 Aug 18;82(16):3061-3076.e6. doi: 10.1016/j.molcel.2022.06.030.
Consuelo Torrini 1,  Trang Thi Thu Nguyen 1,  Chang Shu 1,  Angeliki Mela 1,  Nelson Humala 2,  Aayushi Mahajan 2,  Erin Heather Seeley 3,  Guoan Zhang 4,  Mike-Andrew Westhoff 5,  Georg Karpel-Massler 6,  Jeffrey N Bruce 2,  Peter Canoll 1,  Markus D Siegelin 7
Affiliations

Affiliations

  • 1 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
  • 2 Department of Neurological Surgery, Columbia University Medical Center, New York, NY 10032, USA.
  • 3 Department of Chemistry, University of Texas at Austin, Austin, TX 78712, USA.
  • 4 Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10021, USA.
  • 5 Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, 89081 Ulm, Germany.
  • 6 Department of Neurosurgery, Ulm University Medical Center, 89081 Ulm, Germany.
  • 7 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: ms4169@cumc.columbia.edu.
PMID: 35948010 DOI: 10.1016/j.molcel.2022.06.030
Abstract

Lactate accumulates to a significant amount in glioblastomas (GBMs), the most common primary malignant brain tumor with an unfavorable prognosis. However, it remains unclear whether lactate is metabolized by GBMs. Here, we demonstrated that lactate rescued patient-derived xenograft (PDX) GBM cells from nutrient-deprivation-mediated cell death. Transcriptome analysis, ATAC-seq, and ChIP-seq showed that lactate entertained a signature of oxidative energy metabolism. LC/MS analysis demonstrated that U-13C-lactate elicited substantial labeling of TCA-cycle metabolites, acetyl-CoA, and histone protein acetyl-residues in GBM cells. Lactate enhanced chromatin accessibility and histone acetylation in a manner dependent on oxidative energy metabolism and the ATP-citrate lyase (ACLY). Utilizing orthotopic PDX models of GBM, a combined tracer experiment unraveled that lactate carbons were substantially labeling the TCA-cycle metabolites. Finally, pharmacological blockage of oxidative energy metabolism extended overall survival in two orthotopic PDX models in mice. These results establish lactate metabolism as a novel druggable pathway for GBM.

Keywords

ATAC-seq; ChIP-seq; glioblastoma; lactate; metabolic flux analysis; tumor metabolism.

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