Increased mitochondrial activity in a novel IDH1-R132H mutant human oligodendroglioma xenograft model: In situ detection of 2-HG and α-KG

Anna C. Navis, Simone P. Niclou, Fred Fack, Daniel Stieber, Sanne van Lith, Kiek Verrijp, Alan Wright, Jonathan Stauber, Bastiaan Tops, Irene Otte-Holler, Ron A. Wevers, Arno van Rooij, Stefan Pusch, Andreas von Deimling, Wikky Tigchelaar, Cornelis J.F. van Noorden, Pieter Wesseling, William P.J. Leenders*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

43 Citations (Scopus)

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.

Original languageEnglish
Article number18
JournalActa neuropathologica communications
Volume2
Issue number1
DOIs
Publication statusPublished - 27 Jan 2014

Keywords

  • D-2-hydroxyglutarate
  • Glioma
  • IDH mutations
  • Mitochondria: LESA-nano ESI-FTICR
  • Xenograft
  • α-ketoglutarate

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