In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors

Publication date: Available online 19 October 2017
Source:Cell Metabolism
Author(s): Lucia Salamanca-Cardona, Hardik Shah, Alex J. Poot, Fabian M. Correa, Valentina Di Gialleonardo, Hui Lui, Vesselin Z. Miloushev, Kristin L. Granlund, Sui S. Tee, Justin R. Cross, Craig B. Thompson, Kayvan R. Keshari
The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutamine in vitro. Then, using hyperpolarized magnetic resonance imaging (HP-MRI), we demonstrate that in vivo HP [1-¹³C] glutamine can be used to non-invasively measure glutamine-derived HP 2-HG production. This can be readily modulated utilizing a selective IDH1 inhibitor, opening the door to targeting glutamine-derived 2-HG therapeutically. Rapid rates of HP 2-HG generation in vivo further demonstrate that, in a context-dependent manner, glutamine can be a primary carbon source for 2-HG production in mutant IDH tumors.

Graphical abstract

Teaser

Salamanca-Cardona et al. show that glutamine is a primary carbon source for the biosynthesis of the oncometabolite 2-hydroxyglutarate in mutant IDH tumors. They develop a novel hyperpolarized MRI method using glutamine as a probe to detect 2-hydroxyglutarate formation in vivo in real time, non-invasively, and with high specificity.


http://ift.tt/2yw1RWv