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WIREs Syst Biol Med
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Metabolic interactions in cancer: cellular metabolism at the interface between the microenvironment, the cancer cell phenotype and the epigenetic landscape

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Metabolism is tied into complex interactions with cell intrinsic and extrinsic processes that go beyond the conversion of nutrients into energy and biomass. Indeed, metabolism is a central cellular hub that interconnects and influences the microenvironment, the cellular phenotype, cell signaling, and the (epi)genetic landscape. While these interactions evolved to support survival and function of normal cells, they are hijacked by cancer cells to enable cancer maintenance and progression. Thus, a mechanistic and functional understanding of complex metabolic interactions provides a basis for the discovery of novel metabolic vulnerabilities in cancer. In this review, we will summarize and provide context for the to‐date discovered complex metabolic interactions by discussing how the microenvironment as well as the cellular phenotype define cancer metabolism, and how metabolism shapes the epigenetic state of cancer cells. Many of the studies investigating the crosstalk of metabolism with cell intrinsic and extrinsic processes have used integrative data analysis approaches at the interface between computational and experimental cancer research, and we will highlight those throughout the review. In conclusion, identifying and understanding complex metabolic interactions is a basis for deciphering novel metabolic vulnerabilities of cancer cells.

Metabolism is defined by the microenvironment. The in vitro and in vivo microenvironment enforces a different nutrient usage in cancer cells. The depicted in vivo changes have been observed when cancer cells (originating from breast or lung cancers) proliferate in the lung microenvironment. Arrows thickness depicts flux magnitude. Black arrows represent metabolic pathways. Colored arrows represent the contribution of different extracellular nutrients to intracellular metabolism. Metabolic enzymes connected to the observed flux changes are depicted in blue. Only a selection of metabolic reaction within central metabolism is depicted. Abbreviations: AcCoA, acetyl‐CoA; Asp, aspartate; BCAA, branched‐chain amino acid; BCAT, branched‐chain amino acid transaminase 1; Gln, glutamine; GLS1, glutaminase1; Lac, lactate; LDH, lactate dehydrogenase; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; Pyr, pyruvate; TCA cycle, tricarboxylic acid cycle.
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Metabolism is defining the epigenetic state of a cell. (a,b) Metabolic regulation of DNA/histone methylation and demethylation. (c,d) Metabolic regulation of histone acetylation and deacetylation. TET enzymes and DMNTs target DNA, while JHDMs, HMTs, and HATs target histones. Enzymes are depicted in blue. Methylation is depicted in red. Hydroxymethylation is depicted in green. Acetylation is depicted in yellow. Only a selection of metabolic reaction within central metabolism is depicted. Abbreviations: 2‐HG, 2‐hydroxyglutaric acid; AcCoA, acetyl‐CoA; ACLY, ATP‐citrate lyase; ACSS2, AcCoA synthetase 2; DNMTs, DNA methyltransferase; HATs, histone acetyltransferases; HMTs, histone methyltransferases; JHDMs, Jumonji‐C (JmjC) domain‐containing histone demethylases; NAD+, nicotinamide adenine dinucleotide; SAM, S‐adenosyl methionine; TCA cycle, tricarboxylic acid cycle; TET, ten–eleven translocation enzymes; THF, tetrahydrofolate.
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Metabolism is defined by the cellular phenotype. (a) Metabolic differences observed in colonizing cancer cells compared to colony forming nontransformed cells grown in 3D culture are depicted. (b) Metabolic differences observed in colonizing (3D) cancer cells compared to proliferating (2D) cancer cells are depicted. Black arrows represent metabolic pathways of central carbon metabolism. Arrows thickness depicts flux magnitude. Colored arrows represent the contribution of different extracellular nutrients to intracellular metabolism. Metabolic enzymes connected to the observed flux changes are depicted in blue. Oncogenic signaling pathways are depicted in green. Only a selection of metabolic reaction within central metabolism is depicted. Abbreviations: αKG, α‐ketoglutaric acid; AcCoA, acetyl‐CoA; ATP, adenosine triphosphate; Cit, citrate; ETC, electron transport chain; FADH2, Dihydroflavine‐adenine dinucleotide; Lac, lactate; NADP+, nicotinamide adenine dinucleotide phosphate; NADPH, reduced NADP+; P5C, pyrroline 5 carboxylic acid; PDH, pyruvate dehydrogenase; PPP, pentose phosphate pathway; Pro, proline; PRODH, proline dehydrogenase; Pyr, pyruvate; TCA cycle, tricarboxylic acid cycle.
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Biological Mechanisms > Metabolism
Physiology > Mammalian Physiology in Health and Disease

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In the Spotlight

Jens Nielsen

Jens Nielsen
is a Professor in the Department of Biology and Biological Engineering at Chalmers University of Technology in Göteborg, Sweden. His research focus is on systems biology of metabolism. The yeast Saccharomyces cerevisiae is the lab’s key organism for experimental research, but they also work with Aspergilli oryzae.

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