Dataset Information

Metabolic imaging using hyperpolarized ¹³ C-pyruvate to assess sensitivity to the B-Raf inhibitor vemurafenib in melanoma cells and xenografts.

ABSTRACT: Nearly all melanoma patients with a BRAF-activating mutation will develop resistance after an initial clinical benefit from BRAF inhibition (BRAFi). The aim of this work is to evaluate whether metabolic imaging using hyperpolarized (HP) ¹³ C pyruvate can serve as a metabolic marker of early response to BRAFi in melanoma, by exploiting the metabolic effects of BRAFi. Mice bearing human melanoma xenografts were treated with the BRAFi vemurafenib or vehicle. In vivo HP ¹³ C magnetic resonance spectroscopy was performed at baseline and 24 hours after treatment to evaluate changes in pyruvate-to-lactate conversion. Oxygen partial pressure was measured via electron paramagnetic resonance oximetry. Ex vivo qRT-PCR, immunohistochemistry and WB analysis were performed on tumour samples collected at the same time-points selected for in vivo experiments. Similar approaches were applied to evaluate the effect of BRAFi on sensitive and resistant melanoma cells in vitro, excluding the role of tumour microenvironment. BRAF inhibition induced a significant increase in the HP pyruvate-to-lactate conversion in vivo, followed by a reduction of hypoxia. Conversely, the conversion was inhibited in vitro, which was consistent with BRAFi-mediated impairment of glycolysis. The paradoxical increase of pyruvate-to-lactate conversion in vivo suggests that such conversion is highly influenced by the tumour microenvironment.

SUBMITTER: Acciardo S

PROVIDER: S-EPMC6991684 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Metabolic imaging using hyperpolarized 13 C-pyruvate to assess sensitivity to the B-Raf inhibitor vemurafenib in melanoma cells and xenografts.

Acciardo Stefania S Mignion Lionel L Lacomblez Estelle E Schoonjans Céline C Joudiou Nicolas N Gourgue Florian F Bouzin Caroline C Baurain Jean-François JF Gallez Bernard B Jordan Bénédicte F BF

Journal of cellular and molecular medicine 20191213 2

Nearly all melanoma patients with a BRAF-activating mutation will develop resistance after an initial clinical benefit from BRAF inhibition (BRAFi). The aim of this work is to evaluate whether metabolic imaging using hyperpolarized (HP) 13 C pyruvate can serve as a metabolic marker of early response to BRAFi in melanoma, by exploiting the metabolic effects of BRAFi. Mice bearing human melanoma xenografts were treated with the BRAFi vemurafenib or vehicle. In vivo HP 13 C ma ...[more]

PMID: 31833658

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Project description:The detection and treatment monitoring of inflammatory states remain challenging in part due to the multifactorial mechanisms of immune activation and spectrum of clinical manifestations. Currently, diagnostic strategies tend to be subjective and limited quantitative tools exist to monitor optimal treatment strategies. Pro-inflammatory M1 polarized macrophages exhibit a distinct metabolic glycolytic phenotype compared to the continuum of M2 polarization states. In the present study, the distinct metabolic phenotypes of resting and activated macrophages were successfully characterized and quantified using hyperpolarized carbon-13 (13C) labeled pyruvate and its metabolic products, i.e. lactate, as a biomarker of resting, disease and treated states. Methods: Mouse macrophage J774A.1 cells were used as a model system in an NMR compatible bioreactor to facilitate dynamic hyperpolarized 13C measurements. The glycolytic metabolism of the cells in the quiescent or resting state were compared with macrophages stimulated by lipopolysaccharide, a classical M1 activator using hyperpolarized 13C labeled pyruvate. Additionally, the activated macrophages were also treated with a non-steroidal anti-inflammatory drug to assess the changes in hyperpolarized lactate signal. The hyperpolarized lactate signals were then correlated using biochemical and molecular assays. Results: We first validated our model system of inflammatory cells by the hallmarks of M1 polarization using steady state metabolic profiling with high resolution NMR in conjunction with nitric oxide Greiss assay, enzyme activity, and mRNA expression. Subsequently, we clearly showed that the cutting edge technology of hyperpolarized 13C NMR can be used to detect elevated lactate levels in M1 polarized macrophages in comparison to control and non-steroidal anti-inflammatory drug treated M2 states. Conclusion: Hyperpolarized 13C lactate has the potential to serve as a biomarker to non-invasively detect and quantify pro-inflammatory state of immune regulatory cells and its response to therapy.

Dataset Information

Metabolic imaging using hyperpolarized ¹³ C-pyruvate to assess sensitivity to the B-Raf inhibitor vemurafenib in melanoma cells and xenografts.

Publications

Metabolic imaging using hyperpolarized <sup>13</sup> C-pyruvate to assess sensitivity to the B-Raf inhibitor vemurafenib in melanoma cells and xenografts.

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