1. Spatially Resolved Bioenergetic and Genetic Reprogramming Through the Brain of Rats Bearing Implanted C6 Gliomas As Detected by Multinuclear High-Resolution Magic Angle Spinning and Genomic Analysis
- Author
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Sebastián Cerdán, Pilar López-Larrubia, María-Luisa García-Martín, Vitaliano Tugnoli, Adele Mucci, Valeria Righi, Luisa Schenetti, Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Ministerio de Ciencia y Tecnología (España), Ministerio de Ciencia, Innovación y Universidades (España), Righi, Valeria, Garciá-Martín, Mariá-Luisa, Mucci, Adele, Schenetti, Luisa, Tugnoli, Vitaliano, Lopez-Larrubia, Pilar, and Cerdán, Sebastián
- Subjects
0301 basic medicine ,Bioenergetics ,Biopsy ,Biochemistry ,Oxidative Phosphorylation ,0302 clinical medicine ,Gene expression ,Basic Helix-Loop-Helix Transcription Factors ,Glycolysis ,Carbon Isotopes ,Brain Neoplasms ,Chemistry ,C6 glioma ,HRMAS ,genetic reprogramming ,genomics ,metabolic reprogramming ,metabolomics ,Chemistry (all) ,Metabolic reprogramming ,Glioma ,Genomics ,Cellular Reprogramming ,Magnetic Resonance Imaging ,Phenotype ,030220 oncology & carcinogenesis ,Female ,Transplantation, Heterologous ,Glutamic Acid ,Metabolomic ,Oxidative phosphorylation ,03 medical and health sciences ,Metabolomics ,Animals ,Humans ,Lactic Acid ,Rats, Wistar ,Gene ,Gene Expression Profiling ,Colocalization ,General Chemistry ,Hypoxia-Inducible Factor 1, alpha Subunit ,Molecular biology ,Rats ,Genetic reprogramming ,Glucose ,030104 developmental biology ,Gene Expression Regulation ,Genomic ,Caudate Nucleus ,Neoplasm Transplantation ,Transcription Factors - Abstract
We used 1H, 13C HRMAS and genomic analysis to investigate regionally the transition from oxidative to glycolytic phenotype and its relationship with altered gene expression in adjacent biopsies through the brain of rats bearing C6 gliomas. Tumor-bearing animals were anesthetized and infused with a solution of [1-13C]-glucose, and small adjacent biopsies were obtained spanning transversally from the contralateral hemisphere (regions I and II), the right and left peritumoral areas (regions III and V, respectively), and the tumor core (region IV). These biopsies were analyzed by 1H, 13C HRMAS and by quantitative gene expression techniques. Glycolytic metabolism, as reflected by the [3-13C]-lactate content, increased clearly from regions I to IV, recovering partially to physiological levels in region V. In contrast, oxidative metabolism, as reflected by the [4-13C]-glutamate labeling, decreased in regions I-IV, recovering partially in region V. This metabolic shift from normal to malignant metabolic phenotype paralleled changes in the expression of HIF1α, HIF2α, HIF3α genes, downstream transporters, and regulatory glycolytic, oxidative, and anaplerotic genes in the same regions. Together, our results indicate that genetic and metabolic alterations occurring in the brain of rats bearing C6 gliomas colocalize in situ and the profile of genetic alterations in every region can be inferred from the metabolomic profiles observed in situ by multinuclear HRMAS., The present work was supported by grants SAF2014-53739-R, SAF2017-83043-R, and B2017/BMD-3688 from the Ministry of Economy and Competitiveness and from the Community of Madrid to PL-L and SC, Acciones Integradas IH-HI2006-0101 from the Ministry of Science and Technology to L.S. and S.C. The authors are indebted to Mr. Javier Pérez CSIC for careful drafting of the illustrations and to Mrs. Teresa Navarro CSIC for granting access to the Biomedical NMR Services of the Institute of Biomedical Research “Alberto Sols” CSIC.
- Published
- 2018
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