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

Anna C Navis (1), Simone P Niclou (2), Fred Fack (2), Daniel Stieber (2), Sanne van Lith (1), Kiek Verrijp (1), Alan Wright (3), Jonathan Stauber (4), Bastiaan Tops (1), Irene Otte-Holler (1), Ron A Wevers (5), Arno van Rooij (5), Stefan Pusch (6,7), Andreas von Deimling (6,7), Wikky Tigchelaar (8), Cornelis JF van Noorden (8), Pieter Wesseling (1,9) and William PJ Leenders (1)

1 Department of Pathology, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen, 6500 HB, The Netherlands
2 Centre de Recherche Public de la Santé¸ (CRP-Santé¸), Department of Oncology, NorLux Neuro-Oncology Laboratory, Luxembourg, Luxembourg
3 Department of Radiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
4 IMABIOTECH, Loos, France
5 Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
6 Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 224, Heidelberg, 69120, Germany
7 Clinical Cooperation Unit Neuropathology, German Cancer Institute (DKFZ), Im Neuenheimer Feld 224, Heidelberg, 69120, Germany
8 Academic Medical Centre, Department of Cell Biology and Histology, University of Amsterdam, Amsterdam, The Netherlands
9 Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

Abstract
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 ×ñ-ketoglutarate (×ñ-KG) by IDH1-R132H, in the tumor but not in surrounding brain parenchyma. ×ñ-KG levels and total NADP+-dependent IDH activity were similar in IDH1-mutant and -wildtype xenografts, demonstrating that IDH1-mutated cancer cells maintain ×ñ-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.

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