Metabolic profiling of cancer cells reveals genome-wide crosstalk between transcriptional regulators and metabolism

Ortmayr, Karin; Dubuis, Sébastien; Zampieri, Mattia

doi:10.1038/s41467-019-09695-9

Cited by 107 publications

(105 citation statements)

References 69 publications

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“…During these years, the clear role of specific metabolic pathways in driving pro-tumorigenic events including tumor growth, chemoresistance and plasticity, is emerged [19][20][21][22][23][24]. An over-expression of metabolic genes regulating glycolysis, aminoacyl-tRNA biosynthesis, pyrimidine biosynthesis, purine biosynthesis and pentose phosphate pathway characterize tumor tissues compared to normal samples, thus highlighting the hypothesis of a specific metabolic signature at the tumor level [25].…”

Section: Discussionmentioning

confidence: 99%

1H-NMR Based Serum Metabolomics Highlights Different Specific Biomarkers between Early and Advanced Hepatocellular Carcinoma Stages

Casadei-Gardini

Coco

Marisi

et al. 2020

Cancers

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The application of non-targeted serum metabolomics profiling represents a noninvasive tool to identify new clinical biomarkers and to provide early diagnostic differentiation, and insight into the pathological mechanisms underlying hepatocellular carcinoma (HCC) progression. In this study, we used proton Nuclear Magnetic Resonance (1H-NMR) Spectroscopy and multivariate data analysis to profile the serum metabolome of 64 HCC patients, in early (n = 28) and advanced (n = 36) disease stages. We found that 1H-NMR metabolomics profiling could discriminate early from advanced HCC patients with a cross-validated accuracy close to 100%. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed significant changes in serum glucose, lactate, lipids and some amino acids, such as alanine, glutamine, 1-methylhistidine, lysine and valine levels between advanced and early HCC patients. Moreover, in early HCC patients, Kaplan–Meier analysis highlighted the serum tyrosine level as a predictor for overall survival (OS). Overall, our analysis identified a set of metabolites with possible clinical and biological implication in HCC pathophysiology.

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Section: Discussionmentioning

confidence: 99%

1H-NMR Based Serum Metabolomics Highlights Different Specific Biomarkers between Early and Advanced Hepatocellular Carcinoma Stages

Casadei-Gardini

Coco

Marisi

et al. 2020

Cancers

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“…In the studies that have differentiated between the two, increases in MTA in MTAPhomozygous deleted versus WT cell lines are actually quite modest (Ortmayr et al, 2019).…”

Section: In Vitro Mta Accumulation In Mtap-deleted Cells Is Primarilymentioning

confidence: 99%

Methylthioadenosine is Not Dramatically Elevated inMTAP-Homozygous Deleted Primary Glioblastomas

Barekatain

Yan

Ackroyd

et al. 2019

Preprint

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Highlights• Methylthioadenosine (MTA) is elevated in MTAP-deleted cancer cells in vitro, which provides a selective vulnerability to PRMT5 and MAT2A inhibitors • Accumulation of MTA in MTAP-deleted cancer cells is predominately extracellular, suggesting active secretion of MTA.• MTAP-deleted primary human glioblastoma tumors show minimal intratumoral elevations of MTA, which is likely explained by secretion and metabolism by MTAP-competent stromal cells. SUMMARYHomozygous deletion of the CDK2NA locus frequently results in co-deletion of methylthioadenosine phosphorylase (MTAP) in many fatal cancers such as glioblastoma multiforme (GBM), resulting in elevations of the substrate metabolite, methylthioadenosine (MTA). To capitalize on such accumulations, therapeutic targeting of protein arginine methyltransferase 5 (PRMT5) and methionine adenosyl transferase (MAT2A) are ongoing. While extensively corroborated in vitro, the clinical efficacy of these strategies ultimately relies on equally significant accumulations of MTA in human tumors.Here, we show that in vitro accumulation of MTA is a predominately extracellular phenomenon, indicating secretion of MTA from MTAP-deleted cells. In primary human GBMs, we find that MTA levels are not significantly higher in MTAP-deleted compared to MTAP-intact tumors or normal brain tissue. Together, these findings highlight the metabolic discrepancies between in vitro models and primary human tumors and should thus be carefully considered in the development of the precision therapies targeting MTAP-homozygous deleted GBM.

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“…Recent developments in gene essentiality screening have enabled the identification of novel gene dependencies in cancer cell lines (22)(23)(24)(25). Because DGSEA can identify the metabolic tradeoff between glycolysis and oxidative phosphorylation, we hypothesized that DGSEA would identify different essential genes than GSEA using either glycolysis or oxidative phosphorylation alone.…”

Section: Dgsea Provides Novel Insight Into the Metabolic Dependenciesmentioning

confidence: 99%

Differential Gene Set Enrichment Analysis: A statistical approach to quantify the relative enrichment of two gene sets

Joly

Lowry²,

Graham

2019

Preprint

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Gene Set Enrichment Analysis (GSEA) is an algorithm widely used to identify statistically enriched gene sets in transcriptomic data. However, to our knowledge, there exists no method for examining the enrichment of two gene sets relative to one another. Here, we present Differential Gene Set Enrichment Analysis (DGSEA), an adaptation of GSEA that assesses the relative enrichment of two gene sets. Using the metabolic pathways glycolysis and oxidative phosphorylation as an example, we demonstrate that DGSEA accurately captures the hypoxiainduced shift towards glycolysis. We also show that DGSEA is more predictive than GSEA of the metabolic state of cancer cell lines, including lactate secretion and intracellular concentrations of lactate and AMP. Furthermore, we demonstrate that DGSEA identifies novel metabolic dependencies not found by GSEA in cancer cell lines. Together, these data demonstrate that DGSEA is a novel tool to examine the relative enrichment of two gene sets.

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Metabolic profiling of cancer cells reveals genome-wide crosstalk between transcriptional regulators and metabolism

Cited by 107 publications

References 69 publications

1H-NMR Based Serum Metabolomics Highlights Different Specific Biomarkers between Early and Advanced Hepatocellular Carcinoma Stages

1H-NMR Based Serum Metabolomics Highlights Different Specific Biomarkers between Early and Advanced Hepatocellular Carcinoma Stages

Methylthioadenosine is Not Dramatically Elevated inMTAP-Homozygous Deleted Primary Glioblastomas

Differential Gene Set Enrichment Analysis: A statistical approach to quantify the relative enrichment of two gene sets

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