Journal Article

DKFZ-2017-03069

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Spinal Myxopapillary Ependymomas Demonstrate a Warburg Phenotype.

Mack, S. C. ; Agnihotri, S. ; Bertrand, K. C. ; Wang, X. ; Shih, D. J. ; Witt, H.DKFZ* ; Hill, N. ; Zayne, K. ; Barszczyk, M. ; Ramaswamy, V. ; Remke, M. ; Thompson, Y. ; Ryzhova, M.DKFZ* ; Massimi, L. ; Grajkowska, W. ; Lach, B. ; Gupta, N. ; Weiss, W. A. ; Guha, A. ; Hawkins, C. ; Croul, S. ; Rutka, J. T. ; Pfister, S.DKFZ* ; Korshunov, A.DKFZ* ; Pekmezci, M. ; Tihan, T. ; Philips, J. J. ; Jabado, N. ; Zadeh, G. ; Taylor, M. D.

2015
AACR Philadelphia, Pa. [u.a.]

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Please use a persistent id in citations: doi:10.1158/1078-0432.CCR-14-2650

Abstract: 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.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.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.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.

Keyword(s): HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; Hexokinase ; Protein-Serine-Threonine Kinases ; pyruvate dehydrogenase (acetyl-transferring) kinase

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Contributing Institute(s):

1. Pädiatrische Neuroonkologie (B062)
2. KKE Neuropathologie (G380)
3. DKTK Heidelberg (L101)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2015

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Database coverage:
; BIOSIS Previews ; Current Contents - Clinical Medicine ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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