eprintid: 19451
rev_number: 15
eprint_status: archive
userid: 1589
dir: disk0/00/01/94/51
datestamp: 2016-01-14 09:42:56
lastmod: 2024-04-15 03:39:39
status_changed: 2016-01-14 09:42:56
type: article
metadata_visibility: show
creators_name: Navis, Anna C.
creators_name: Niclou, Simone P.
creators_name: Fack, Fred
creators_name: Stieber, Daniel
creators_name: van Lith, Sanne
creators_name: Verrijp, Kiek
creators_name: Wright, Alan
creators_name: Stauber, Jonathan
creators_name: Tops, Bastiaan
creators_name: Otte-Holler, Irene
creators_name: Wevers, Ron A.
creators_name: van Rooij, Arno
creators_name: Pusch, Stefan
creators_name: von Deimling, Andreas
creators_name: Tigchelaar, Wikky
creators_name: van Noorden, Cornelis JF
creators_name: Wesseling, Pieter
creators_name: Leenders, William PJ
title: Increased mitochondrial activity in a novel IDH1-R132H mutant human oligodendroglioma xenograft model: in situ detection of 2-HG and α-KG
subjects: ddc-610
divisions: i-850300
divisions: i-912000
abstract: Background: Point mutations in genes encoding NADP+-dependent isocitrate dehydrogenases (especially IDH1) are common in lower grade diffuse gliomas and secondary glioblastomas and occur early during tumor development. The contribution of these mutations to gliomagenesis is not completely understood and research is hampered by the lack of relevant tumor models. We previously described the development of the patient-derived high-grade oligodendroglioma xenograft model E478 that carries the commonly occurring IDH1-R132H mutation. We here report on the analyses of E478 xenografts at the genetic, histologic and metabolic level.   Results: LC-MS and in situ mass spectrometric imaging by LESA-nano ESI-FTICR revealed high levels of the proposed oncometabolite D-2-hydroxyglutarate (D-2HG), the product of enzymatic conversion of α-ketoglutarate (α-KG) by IDH1-R132H, in the tumor but not in surrounding brain parenchyma. α-KG levels and total NADP+-dependent IDH activity were similar in IDH1-mutant and -wildtype xenografts, demonstrating that IDH1-mutated cancer cells maintain α-KG levels. Interestingly, IDH1-mutant tumor cells in vivo present with high densities of mitochondria and increased levels of mitochondrial activity as compared to IDH1-wildtype xenografts. It is not yet clear whether this altered mitochondrial activity is a driver or a consequence of tumorigenesis.   Conclusions: The oligodendroglioma model presented here is a valuable model for further functional elucidation of the effects of IDH1 mutations on tumor metabolism and may aid in the rational development of novel therapeutic strategies for the large subgroup of gliomas carrying IDH1 mutations.  
date: 2013
publisher: BioMed Central
id_scheme: DOI
ppn_swb: 1653735570
own_urn: urn:nbn:de:bsz:16-heidok-194516
language: eng
bibsort: NAVISANNACINCREASEDM2013
full_text_status: public
publication: Acta Neuropathologica Communications
volume: 1
number: 18
place_of_pub: London
pagerange: 1-12
issn: 2051-5960
citation:   Navis, Anna C. ; Niclou, Simone P. ; Fack, Fred ; Stieber, Daniel ; van Lith, Sanne ; Verrijp, Kiek ; Wright, Alan ; Stauber, Jonathan ; Tops, Bastiaan ; Otte-Holler, Irene ; Wevers, Ron A. ; van Rooij, Arno ; Pusch, Stefan ; von Deimling, Andreas ; Tigchelaar, Wikky ; van Noorden, Cornelis JF ; Wesseling, Pieter ; Leenders, William PJ  (2013) Increased mitochondrial activity in a novel IDH1-R132H mutant human oligodendroglioma xenograft model: in situ detection of 2-HG and α-KG.  Acta Neuropathologica Communications, 1 (18).  pp. 1-12.  ISSN 2051-5960     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/19451/1/40478_2013_Article_16.pdf