The landscape of metabolic pathway dependencies in cancer cell lines

Joly, James H.; Chew, Brandon; Graham, Nicholas A.

doi:10.1371/journal.pcbi.1008942

Cited by 12 publications

(8 citation statements)

References 54 publications

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“…Over recent months, more than 1300 metabolic reactions and 120 metabolic enzymes have been integrated into the human causal interactome. The enzymatic reactions have been organized into nine pathways, concentrating on pathways whose activities are deregulated in cancer cells (glycolysis and gluconeogenesis, citric acid cycle, glycogenesis, glycogenolysis, aspartate and asparagine metabolism, fatty acid synthesis, glutamine metabolism, nucleotide biosynthesis, pentose phosphate ( Joly, Chew, and Graham 2021 ). In addition, we have identified, in each pathway, key enzymes whose activities are rate limiting and are therefore more likely to affect the metabolic flux when their concentrations or activities are modulated ( Supplementary Table S1 ).…”

Section: Resultsmentioning

confidence: 99%

A Resource to Infer Molecular Paths Linking Cancer Mutations to Perturbation of Cell Metabolism

Iannuccelli

Surdo

Licata

et al. 2022

Front. Mol. Biosci.

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Some inherited or somatically-acquired gene variants are observed significantly more frequently in the genome of cancer cells. Although many of these cannot be confidently classified as driver mutations, they may contribute to shaping a cell environment that favours cancer onset and development. Understanding how these gene variants causally affect cancer phenotypes may help developing strategies for reverting the disease phenotype. Here we focus on variants of genes whose products have the potential to modulate metabolism to support uncontrolled cell growth. Over recent months our team of expert curators has undertaken an effort to annotate in the database SIGNOR 1) metabolic pathways that are deregulated in cancer and 2) interactions connecting oncogenes and tumour suppressors to metabolic enzymes. In addition, we refined a recently developed graph analysis tool that permits users to infer causal paths leading from any human gene to modulation of metabolic pathways. The tool grounds on a human signed and directed network that connects ∼8400 biological entities such as proteins and protein complexes via causal relationships. The network, which is based on more than 30,000 published causal links, can be downloaded from the SIGNOR website. In addition, as SIGNOR stores information on drugs or other chemicals targeting the activity of many of the genes in the network, the identification of likely functional paths offers a rational framework for exploring new therapeutic strategies that revert the disease phenotype.

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Section: Resultsmentioning

confidence: 99%

A Resource to Infer Molecular Paths Linking Cancer Mutations to Perturbation of Cell Metabolism

Iannuccelli

Surdo

Licata

et al. 2022

Front. Mol. Biosci.

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“…Plasma metabolomic profiling provides a snapshot of metabolic changes [ 35 ], which are a good choice for the investigation on diseases and responses to treatment [ 36 ]. We identified 3 metabolic pathways that were significantly altered by HDMTX.…”

Section: Discussionmentioning

confidence: 99%

Metabolic profiling reveals metabolic features of consolidation therapy in pediatric acute lymphoblastic leukemia

Zhang

Liu

et al. 2023

Cancer Metab

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Acute lymphoblastic leukemia (ALL) and its treatment continue to pose substantial risks. To understand ALL more deeply, the metabolome in fasting plasma of 27 ALL patients before and after high-dose methotrexate therapies (consolidation therapy) including methotrexate and 6-mercaptopurine (6-MP) was investigated. Plasma metabolites were analyzed using liquid chromatography–tandem mass spectrometry (LC–MS). Orthogonal projections to latent structures discriminant analysis and significance analysis of microarrays were used to evaluate the metabolic changes. Pathway enrichment and co-expression network analyses were performed to identify clusters of molecules, and 2826 metabolites were identified. Among them, 38 metabolites were identified by univariate analysis, and 7 metabolites that were altered by conditioning therapy were identified by multivariate analysis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used for pathway enrichment analysis. Among the enriched KEGG pathways, the 3 significantly altered metabolic pathways were pyrimidine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; and phenylalanine metabolism. In addition, L-phenylalanine was significantly correlated with blood urea nitrogen (BUN), and palmitoylcarnitine was correlated with aspartate aminotransferase (AST). In summary, consolidation therapy significantly affected pyrimidine- and phenylalanine-associated metabolic pathways in pediatric ALL patients. These findings may provide an insight into the role of metabolic profiling in consolidation treatment and as a potential for pediatric ALL patients.

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“…Combined with the previous KEGG pathway enrichment analyses, the present observations indicated that GDY-Cu mainly caused intracellular fatty acid and lipid metabolism in cancer cells. Metabolic reprogramming is a complex biological process in which various metabolic pathways interact with each other [55]. Aerobic glycolysis plays a vital role in the development of PCa.…”

Section: Untargeted Metabolomics Analysis Reveals Alterations In Du14...mentioning

confidence: 99%

Untargeted metabolomics to analyze alterations in two-dimensional graphdiyne–copper nanocomposite on the metabolic reprogramming of prostate cancer

Zhang¹,

Xie²,

Lin³

et al. 2022

2D Mater.

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Prostate cancer (PCa) is a common type of cancer in men worldwide. Metabolic reprogramming is an important factor in its pathogenesis. Two-dimensional (2D) nanomaterials have tremendous potential for cancer treatment owing to their unique physicochemical properties. However, very few studies have focused on the metabolic reprogramming mechanisms of PCa using 2D nanomaterials. In this study, for the first time, 2D graphdiyne (GDY) was used as a template to immobilize copper (Cu) ions to form a novel nanocomposite (GDY-Cu). GDY provides a large π-conjugated architecture that spatiotemporally restricts Cu ions spatiotemporally to realize the functional moiety of Cu ions as tumor therapeutics. The GDY-Cu nanocomposite with a 2D morphological structure was characterized using a transmission electron microscopy and atomic force microscopy. The distribution of Cu loaded on the GDY was confirmed by high-resolution transmission electron microscopy with energy-dispersive x-ray spectroscopy analysis. In vitro and in vivo, GDY-Cu exhibits a good antitumor effect and is associated with specific metabolic reprogramming characteristics of PCa. In this study, the effect of GDY-Cu on the metabolic reprogramming of PCa cells was analyzed using untargeted metabolomics. Differences in metabolites in DU145 cells treated with GDY-Cu were analyzed by clustering and target analysis using bioinformatics methods. GDY-Cu inhibited the growth of PCa cells by decreasing the expression levels of acetyl-CoA carboxylase and cytoplasmic acetyl-CoA synthase, which inhibits the synthesis of related fatty acids and lipid metabolism. These results indicated that GDY-Cu inhibits the growth of PCa cells mainly via lipid metabolic pathways. At present, combinatory therapeutic modalities based on GDY and Cu are in their infancy. Further exploration is required to promote the development of 2D nanocomposite combinatory therapeutic modalities based on metabolic reprogramming.

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The landscape of metabolic pathway dependencies in cancer cell lines

Cited by 12 publications

References 54 publications

A Resource to Infer Molecular Paths Linking Cancer Mutations to Perturbation of Cell Metabolism

A Resource to Infer Molecular Paths Linking Cancer Mutations to Perturbation of Cell Metabolism

Metabolic profiling reveals metabolic features of consolidation therapy in pediatric acute lymphoblastic leukemia

Untargeted metabolomics to analyze alterations in two-dimensional graphdiyne–copper nanocomposite on the metabolic reprogramming of prostate cancer

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