Glucose metabolic profiles evaluated by PET associated with molecular characteristic landscape of gastric cancer
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ABSTRACT: Although FDG-PET is widely used in cancer, its role in gastric cancer (GC) is still controversial due to variable [18F]fluorodeoxyglucose ([18F]FDG) uptake. Here, we investigate the molecular landscape of GC and its association with glucose metabolic profiles noninvasively evaluated by [18F]FDG PET. Based on a genetic signature, PETscore, representing [18F]FDG avidity, was developed by imaging data acquired from thirty patient-derived xenografts (PDX). Five genes, PLS1, PYY, HBQ1, SLC6A5, NAT16, were identified for the PETscore, which was validated in independent cohorts by qRT-PCR and RNA-sequencing. By applying the PETscore on the Cancer Genome Atlas (TCGA), a significant association between glucose uptake and tumor mutational burden as well as genomic alterations was identified in GC. Our findings suggest that molecular characteristics are underlying the diverse metabolic profiles of GC. Diverse glucose metabolic profiles may apply to precise diagnostic and therapeutic approaches for GC.
Project description:Microglia is dynamically reprogrammed according to the progression of Alzheimer’s disease (AD). However, clinical translation into biomarker development for functional change in microglia has not been achieved. Here, we find the close association of the metabolic reconfiguration of microglia with increased hippocampal glucose uptake, which can be noninvasively estimated by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). We found that increased FDG activity in the hippocampus of an AD mouse model depended on microglial uptake. Single-cell RNA-sequencing of the hippocampus showed the changes of glucose metabolism profiles including glucose transporters, glycolysis and oxidative phosphorylation mainly occurred in microglia. A subset of microglia with high glucose transporters with defective glycolysis and oxidative phosphorylation was increased according to disease progression. Furthermore, we also found a positive association between a soluble TREM2 of cerebrospinal fluid, a marker of microglial activation, and hippocampal FDG uptake as a human study. We identified a reconfiguration of microglial glucose metabolism in the hippocampus of AD and suggested a feasible imaging biomarker based on widely used FDG PET to reflect microglial metabolic profiles.
Project description:We used a positron emission tomography (PET) tracer 18F fluorodeoxyglucose ([18F]-FDG) and transcriptomic analysis to detect glucose uptake by cells in the bone marrow micro-environment with an MLL-AF9-induced mouse model. Leukaemic cells had the greatest glucose uptake. To determine whether glucose uptake is driven by intrinsic demand, we applied RNA-seq of sorted leukaemia cells (GFP+) and bone marrow micro-environment myeloid cells (GFP-CD11b+) from the MLL-AF9 transduced mouse model.
Project description:The standardized uptake value (SUV), an indicator of the glucose uptake degree in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), has been used as a prognostic factor in malignant tumors. We aimed to identify a signature reflecting prognostic SUV characteristics in triple negative breast cancer (TNBC). Transcriptome profiling was performed to identify a signature associated with the SUV in TNBC patients who underwent preoperative FDG-PET. We defined a signature significantly associated with the SUV (|r| > .35; P < .01). The SUV signature showed independent clinical utility for predicting BRC prognosis. Integrative analysis demonstrated a significance of the signature in predicting the response to immunotherapy and revealed that a signaling axis defined by TP53-FOXM1 and its downstream effectors in glycolysis-gluconeogenesis, including LDHA, might be important mediators in the FDG-PET process. Our results reveal characteristics of glucose uptake captured by FDG-PET, supporting an understanding of glucose metabolism as well as poor prognosis in TNBC patients with a high SUV.
Project description:Rationale: Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate receptors ERα and ERβ. Since female sex hormones enhance global glucose utilization and because myocardial function and mass are tightly linked to cardiac glucose metabolism we tested the hypothesis that expression and activation of the estrogen receptor α (ERα) might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Methods and Results: Cardiac glucose uptake quantified in vivo by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was strongly impaired in ovarectomized compared to gonadal intact female C57BL/6JO mice. The selective ERα agonist 16α-LE2 and the non-selective ERα and ERβ agonist 17β-estradiol completely restored cardiac glucose uptake in ovarectomized mice. Cardiac FDG uptake was strongly decreased in female ERα knockout mice (ERKO) compared to wild type littermates. Biochemical assays, affymetrix cDNA array analysis, western blotting and immuno-staining of cardiac glucose transporters revealed a positive correlation of ERα dependent cardiac FDG uptake with preserved cardiac glucose transporter-1 expression and micro-vascular localization. Conclusions: Systemic activation of the ERα estrogen receptor is sufficient and its expression is required to maintain physiological glucose uptake in the murine heart, which is likely to contribute to known cardio-protective estrogen effects. total samples analysed are 20
Project description:The standardized uptake value (SUV), an indicator of the glucose uptake degree in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), has been used as a prognostic factor in malignant tumors. We aimed to identify a signature reflecting prognostic SUV characteristics in breast cancer (BRC). Transcriptome profiling was performed to identify a signature associated with the SUV in BRC patients who underwent preoperative FDG-PET. We defined a signature consisting of 723 genes significantly correlated with the SUV (|r| > .35; P < .001). The patient subgroups classified by the signature were significantly similar to those classified by the SUV (odds ratio, 8.02; 95% CI, 2.45 to 29.3; P < 0.001). The SUV signature showed independent clinical utility for predicting BRC prognosis (hazard ratio, 1.25; 95% CI, 1.11 to 1.42; P < 0.001). Integrative analysis demonstrated a significance of the signature in predicting the response to immunotherapy and revealed that a signaling axis defined by TP53-FOXM1 and its downstream effectors in glycolysis-gluconeogenesis, including LDHA, might be important mediators in the FDG-PET process. Our results reveal characteristics of glucose uptake captured by FDG-PET, supporting an understanding of glucose metabolism as well as poor prognosis in BRC patients with a high SUV.
Project description:Rationale: Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate receptors ERα and ERβ. Since female sex hormones enhance global glucose utilization and because myocardial function and mass are tightly linked to cardiac glucose metabolism we tested the hypothesis that expression and activation of the estrogen receptor α (ERα) might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Methods and Results: Cardiac glucose uptake quantified in vivo by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was strongly impaired in ovarectomized compared to gonadal intact female C57BL/6JO mice. The selective ERα agonist 16α-LE2 and the non-selective ERα and ERβ agonist 17β-estradiol completely restored cardiac glucose uptake in ovarectomized mice. Cardiac FDG uptake was strongly decreased in female ERα knockout mice (ERKO) compared to wild type littermates. Biochemical assays, affymetrix cDNA array analysis, western blotting and immuno-staining of cardiac glucose transporters revealed a positive correlation of ERα dependent cardiac FDG uptake with preserved cardiac glucose transporter-1 expression and micro-vascular localization. Conclusions: Systemic activation of the ERα estrogen receptor is sufficient and its expression is required to maintain physiological glucose uptake in the murine heart, which is likely to contribute to known cardio-protective estrogen effects.
Project description:Aerobic glycolysis is a hallmark of cancer glucose metabolism. Here we suggest that extracellular vesicles (EVs) originating from cancer cells can modulate glucose metabolism in the recipient cancer cells and induce cell proliferation and aggressive cancer phenotypes. Two breast cancer cell lines with different levels of glycolytic activity, MDA-MB-231 and MCF7, were selected and co-cultured, as the originating and recipient cells. The change in 18F-fluorodeoxyglucose (FDG) uptake of the recipient MCF7 cells was assessed after co-culture with the MDA-MB-231 cells. Proteomics analysis was performed to investigate the changes in the protein expression patterns in the recipient MCF7 cells. FDG uptake by the recipient MCF7 cells was sig-nificantly increased after co-culture with the MDA-MB-231 cells.
Project description:This study aims at identifying genes involved in this metabolic activation potentially related to rupture. A genome-wide transcriptomic analysis was performed on biopsies collected from patients with a Fluorodeoxyglucose (FDG) uptake both in the positive spot (A+Pos) and in a distant negative site of the same aneurysm (A+Neg). These paired biopsies were further compared to samples collected from (abdominal aortic aneurysms) AAA patients with no FDG uptake (A0) in order to discriminate biological alterations associated with FDG uptake, to detect new systemic biomarkers correlated with a higher risk of rupture and to identify new pathways involved in the progression and rupture of AAA).
Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.