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Clin Cancer Res. 2015 Aug 15;21(16):3750-8. doi: 10.1158/1078-0432.CCR-14-2650. Epub 2015 May 8.

Spinal Myxopapillary Ependymomas Demonstrate a Warburg Phenotype.

Author information

1
Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
2
Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
3
Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Germany. Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany.
4
Pediatric Neurosurgery, Catholic University Medical School, Gemelli Hospital, Rome, Italy.
5
Department of Pathology University of Warsaw, Children's Memorial Health Institute University of Warsaw, Warsaw, Poland.
6
Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton General Hospital, Hamilton, Ontario, Canada.
7
Departments of Neurology, Pediatrics, Neuro-Pathology and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California.
8
German Cancer Consortium (DKTK), Heidelberg, Germany. CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
9
Departments of Pediatrics and Human Genetics, McGill University and the McGill University Health Center Research Institute, Montreal, Quebec, Canada.
10
Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada. mdtaylor@sickkids.ca.

Abstract

PURPOSE:

Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy.

EXPERIMENTAL DESIGN:

Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production.

RESULTS:

At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production.

CONCLUSIONS:

Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE.

PMID:
25957288
PMCID:
PMC4537825
DOI:
10.1158/1078-0432.CCR-14-2650
[Indexed for MEDLINE]
Free PMC Article

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