TY  - JOUR
AU  - Mack, Stephen C
AU  - Agnihotri, Sameer
AU  - Bertrand, Kelsey C
AU  - Wang, Xin
AU  - Shih, David J
AU  - Witt, Hendrik
AU  - Hill, Nadia
AU  - Zayne, Kory
AU  - Barszczyk, Mark
AU  - Ramaswamy, Vijay
AU  - Remke, Marc
AU  - Thompson, Yuan
AU  - Ryzhova, Marina
AU  - Massimi, Luca
AU  - Grajkowska, Wieslawa
AU  - Lach, Boleslaw
AU  - Gupta, Nalin
AU  - Weiss, William A
AU  - Guha, Abhijit
AU  - Hawkins, Cynthia
AU  - Croul, Sidney
AU  - Rutka, James T
AU  - Pfister, Stefan
AU  - Korshunov, Andrey
AU  - Pekmezci, Melike
AU  - Tihan, Tarik
AU  - Philips, Joanna J
AU  - Jabado, Nada
AU  - Zadeh, Gelareh
AU  - Taylor, Michael D
TI  - Spinal Myxopapillary Ependymomas Demonstrate a Warburg Phenotype.
JO  - Clinical cancer research
VL  - 21
IS  - 16
SN  - 1557-3265
CY  - Philadelphia, Pa. [u.a.]
PB  - AACR
M1  - DKFZ-2017-03069
SP  - 3750 - 3758
PY  - 2015
AB  - 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.
KW  - HIF1A protein, human (NLM Chemicals)
KW  - Hypoxia-Inducible Factor 1, alpha Subunit (NLM Chemicals)
KW  - Hexokinase (NLM Chemicals)
KW  - Protein-Serine-Threonine Kinases (NLM Chemicals)
KW  - pyruvate dehydrogenase (acetyl-transferring) kinase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25957288
C2  - pmc:PMC4537825
DO  - DOI:10.1158/1078-0432.CCR-14-2650
UR  - https://inrepo02.dkfz.de/record/127043
ER  -