title: Increased mitochondrial activity in a novel IDH1-R132H mutant human oligodendroglioma xenograft model: in situ detection of 2-HG and α-KG.
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.
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen, 6500 HB, The Netherlands. W.Leenders@pathol.umcn.nl.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Navis
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
authors.forename: Fred
authors.initials: F
authors.lastname: Fack
authors.forename: Daniel
authors.initials: D
authors.lastname: Stieber
authors.forename: Sanne
authors.initials: S
authors.lastname: van Lith
authors.forename: Kiek
authors.initials: K
authors.lastname: Verrijp
authors.forename: Alan
authors.initials: A
authors.lastname: Wright
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stauber
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Tops
authors.forename: Irene
authors.initials: I
authors.lastname: Otte-Holler
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: Arno
authors.initials: A
authors.lastname: van Rooij
authors.forename: Stefan
authors.initials: S
authors.lastname: Pusch
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Wikky
authors.initials: W
authors.lastname: Tigchelaar
authors.forename: Cornelis J F
authors.initials: CJ
authors.lastname: van Noorden
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.forename: William P J
authors.initials: WP
authors.lastname: Leenders
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D005260:Female; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000502:physiology*; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D009837:Oligodendroglioma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*
chemical_list: D005977:Glutarates; D007656:Ketoglutaric Acids; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human