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000127043 0247_ $$2doi$$a10.1158/1078-0432.CCR-14-2650
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000127043 0247_ $$2ISSN$$a1557-3265
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000127043 037__ $$aDKFZ-2017-03069
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000127043 1001_ $$aMack, Stephen C$$b0
000127043 245__ $$aSpinal Myxopapillary Ependymomas Demonstrate a Warburg Phenotype.
000127043 260__ $$aPhiladelphia, Pa. [u.a.]$$bAACR$$c2015
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000127043 520__ $$aMyxopapillary 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.
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000127043 650_7 $$2NLM Chemicals$$aHIF1A protein, human
000127043 650_7 $$2NLM Chemicals$$aHypoxia-Inducible Factor 1, alpha Subunit
000127043 650_7 $$0EC 2.7.1.1$$2NLM Chemicals$$aHexokinase
000127043 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aProtein-Serine-Threonine Kinases
000127043 650_7 $$0EC 2.7.11.2$$2NLM Chemicals$$apyruvate dehydrogenase (acetyl-transferring) kinase
000127043 7001_ $$aAgnihotri, Sameer$$b1
000127043 7001_ $$aBertrand, Kelsey C$$b2
000127043 7001_ $$aWang, Xin$$b3
000127043 7001_ $$aShih, David J$$b4
000127043 7001_ $$0P:(DE-He78)046fd145f1008f83f6236580727bbc0f$$aWitt, Hendrik$$b5$$udkfz
000127043 7001_ $$aHill, Nadia$$b6
000127043 7001_ $$aZayne, Kory$$b7
000127043 7001_ $$aBarszczyk, Mark$$b8
000127043 7001_ $$aRamaswamy, Vijay$$b9
000127043 7001_ $$aRemke, Marc$$b10
000127043 7001_ $$aThompson, Yuan$$b11
000127043 7001_ $$0P:(DE-HGF)0$$aRyzhova, Marina$$b12
000127043 7001_ $$aMassimi, Luca$$b13
000127043 7001_ $$aGrajkowska, Wieslawa$$b14
000127043 7001_ $$aLach, Boleslaw$$b15
000127043 7001_ $$aGupta, Nalin$$b16
000127043 7001_ $$aWeiss, William A$$b17
000127043 7001_ $$aGuha, Abhijit$$b18
000127043 7001_ $$aHawkins, Cynthia$$b19
000127043 7001_ $$aCroul, Sidney$$b20
000127043 7001_ $$aRutka, James T$$b21
000127043 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b22$$udkfz
000127043 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b23$$udkfz
000127043 7001_ $$aPekmezci, Melike$$b24
000127043 7001_ $$aTihan, Tarik$$b25
000127043 7001_ $$aPhilips, Joanna J$$b26
000127043 7001_ $$aJabado, Nada$$b27
000127043 7001_ $$aZadeh, Gelareh$$b28
000127043 7001_ $$aTaylor, Michael D$$b29
000127043 773__ $$0PERI:(DE-600)2036787-9$$a10.1158/1078-0432.CCR-14-2650$$gVol. 21, no. 16, p. 3750 - 3758$$n16$$p3750 - 3758$$tClinical cancer research$$v21$$x1557-3265$$y2015
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