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How the complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth is explored.

Jason Locasale, Lewis Cantley, Matthew Vander Heiden and colleagues show that PHGDH is amplified in some human cancers and diverts a relatively large amount of glycolytic carbon into serine and glycine biosynthesis. They further show that PHGDH-amplified cancer cells become dependent on PHGDH for their growth, suggesting that the altered metabolic flux driven by this amplification contributes to oncogenesis.

ATP drives most cellular processes, although ATP production and consumption levels during mitosis remain unreported. Here, the authors combine metabolic measurements and modeling to quantify ATP levels and synthesis dynamics, revealing that ATP synthesis and consumption are lowered during mitosis.

Lien et al. show that low glycemic diets can reduce tumour growth by deregulating lipid metabolism.

The non-essential amino acids serine and glycine are critical for proliferative metabolism. A study in Nature now finds that dietary serine and glycine deprivation inhibits growth of some tumours. Whether this dietary intervention is effective depends on both the oncogenic context and tumour tissue of origin.

Cancer cells have adapted metabolically to support their characteristic high rate of proliferation. Targeting the metabolic differences between cancer cells and normal cells is emerging as a promising therapeutic approach. Here, Vander Heiden discusses the associated challenges and limitations of this anticancer strategy and reviews evidence supporting specific metabolic enzymes as potential targets.

Studying patients with long-term diabetes who lack diabetic nephropathy reveals that targeting pyruvate kinase M2 protects against renal disease.

Dietary cysteine enhances intestinal stem cell-mediated intestinal repair following injury by promoting CD8 T cell-regenerative immune responses.

Sullivan and Darnell et al. show that conversion of 5-methyl tetrahydrofolate to tetrahydrofolate by the enzyme methionine synthase is required for tumour growth under physiological folate conditions.

Seemingly unrelated mutations that drive cancer share the ability to promote nutrient uptake and metabolism conducive to cell growth.

Metabolic alterations, such as those caused by mutations in the enzyme isocitrate dehydrogenase (IDH), define a clinically distinct subset of primary brain cancers. Expression of BCAT1 is now reported as a new metabolic change defining brain cancers without IDH mutations (pages 901–908).

Altered cancer cell metabolism can result in intracellular metabolite concentration changes. This Review discusses the mechanisms that lead to metabolite concentration changes in cancer cells, the consequences of these changes and how they might be exploited to improve cancer therapy.

While BH3-mimetics can be effective for treatment of haematological malignancies, their efficacy in solid tumours is limited. Here, using a range of patient-derived prostate cancer models, the authors demonstrate that increased replication stress induced by RB1 loss confers sensitivity to BH3 mimetics targeting BCL-XL.

Diehl et al. show that imbalance among nucleotide species is not sensed by canonical metabolic regulatory pathways, causing excessive cell growth despite a DNA replication block. ATR is needed to increase nucleotide availability in normal S phase.

Electrical excitability in neuroendocrine SCLC cells promotes tumour progression through action potential firing, increasing ATP demand and oxidative phosphorylation dependency, whereas non-neuroendocrine cells provide metabolic support, driving a tumour-autonomous cycle that enhances tumorigenesis and metastasis.

CAR-T therapy is a promising treatment modality for B-cell malignancies, yet many patients relapse. Using an in vivo genomewide screen in a model of B cell leukemia, we identify an unexpected mechanism of CAR-T resistance in which interferon gamma from the in vivo tumor microenvironment induces an adaptive T-cell resistance program in tumor cells.

Metabolites in the tumor microenvironment, including adenosine, have been shown to suppress anti-tumor immune responses. Here, the authors show that T cell expression of the adenosine transporter ENT1 is involved in this immunosuppression and can be targeted to boost T cell function, tumor killing and immune checkpoint blockade.

Mukhopadhyay, Vander Heiden and McCormick review the metabolic landscape of RAS-driven cancers, the effects of RAS-directed metabolic reprogramming and opportunities for targeting these cancers therapeutically.

Positron emission tomography measurements of nutrient uptake in cells of the tumour microenvironment reveal cell-intrinsic partitioning in which glucose uptake is higher in myeloid cells, whereas glutamine is preferentially acquired by cancer cells.

Ferraro et al. report that fatty acid synthesis is needed for brain cancer metastasis and show that blocking this process by inhibiting fatty acid synthase reduces the metastatic growth of breast cancer cells in the brain.

Advanced pancreatic cancer is associated with tissue wasting; however, the timing of tissue loss prior to diagnosis and the potential utility of such loss for earlier pancreatic cancer detection are not well understood. Here the authors show that skeletal muscle loss can be detected on CT imaging 1–2 years before a clinical diagnosis of pancreatic cancer.

Glycolysis is elevated in many cancers. In this study, the authors show that lactoylglutathione, a by-product of methylglyoxal produced from increased glycolysis, is elevated in lung cancer in mouse models and humans, arguing reactive metabolite production can be a liability for cancers.

Pyridoxal 5’-phosphate (PLP, vitamin B6) is crucial for various metabolic processes. Here, the authors identified SLC25A38 as a key regulator of mitochondrial PLP levels using a genome-wide CRISPRi screen and organellar metabolomics, with insights into congenital sideroblastic anemia.

Pancreatic ductal adenocarcinoma in mice induces loss of adipose tissue through altered function of the exocrine pancreas, and supplementing pancreatic enzymes attenuates the wasting of peripheral tissues induced by pancreatic cancer.

Defective proteins or functional proteins that are no longer needed can be degraded in the endoplasmic reticulum. In this study, Lopez-Serra et al.show that DERL3, which is involved in protein degradation in the endoplasmic reticulum, is aberrantly silenced in cancer, leading to activation of a glucose transporter and dysregulated glycolysis.

Post-fast refeeding increases intestinal stem cell function and tumour formation by augmenting protein synthesis via polyamine metabolism.

Proliferating cells of the Xenopus laevis retina facultatively use aerobic glycolysis instead of oxidative phosphorylation. This demonstrates that the metabolic rewiring usually associated with the Warburg effect in tumorigenesis may be a more widespread feature of proliferative metabolism than generally appreciated.

A quantitative high-throughput screen identified an inhibitor of phosphoglycerate dehydrogenase (PHGDH), a key enzyme for serine synthesis. This inhibitor limits one-carbon unit availability for nucleotide synthesis.

Metabolite alterations are crucial for understanding diseases, yet large-scale untargeted metabolomics faces challenges in signal detection and dataset integration. Here, the authors introduce mzLearn, a data-driven MS¹ signal-detection method that that corrects instrumental drift and enhances signal accuracy and consistency, enabling the development of pre-trained models for untargeted metabolomics.

Many tumour cells express the M2 form of pyruvate kinase rather than the usual M1 form. PKM2 is now shown to promote tumorigenesis and switch the cellular metabolism to increased lactate production and reduced oxygen consumption, recapitulating key aspects of the Warburg effect.

A small-molecule activator specific for PKM2 binds to a site distinct from the endogenous activator fructose-1,6-bisphosphate, promoting tetramerization and constitutive activation of PKM2, to inhibit xenograft tumor growth in mice.

Whether Kupffer cells play a role in regulating the pathogenesis of fatty liver disease remains to be completely explored. Here, the authors show GPR3 activation stimulates glycolysis in Kupffer cells through GPR3-β-arrestin2-GAPDHPKM2 pathway and inhibits high-fat diet induced obesity and liver pathogenesis.

Pancreatic ductal adenocarcinoma has a collagen-rich dense extracellular matrix that promotes malignancy of cancer cells. Here, the authors show that fibrillar collagen that is cancer-cell-derived, but not stroma-derived, selectively restrains tumor growth under control of their pC-proteinase, BMP1.

Chidley et al. report a CRISPR interference/activation screening platform to systematically interrogate the contribution of nutrient transporters to support cancer cell proliferation in environments of variable composition.

Cellular metabolism is substantially altered during oncogenesis and tumour progression, and targeting these metabolic changes is being actively pursued in the development of selective antineoplastic agents. Here, Kroemer and colleagues discuss the intimate relationship between metabolism and malignancy, focusing on therapeutic strategies and emerging agents targeting the metabolic rearrangements of cancer cells.

Cell fate commitment involves transcription factor activity and changes in chromatin architecture. Here the authors show that CAF-1 maintains lineage fidelity by controlling chromatin accessibility at specific sites; suppressing CAF-1 triggers differentiation of myeloid stem and progenitor cells into a mixed lineage state.

As solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.

Using patient-derived colorectal cancer tumour enteroids, Schwartz et al. find that ectopic expression of hepcidin in the tumour epithelium establishes an axis to sequester iron to maintain the nucleotide pool and sustain proliferation.

Mitochondria maintain a balance between thermogenesis and ATP synthesis, but how this is coordinated is largely unknown. Here, the authors show that MFSD7C coordinates ATP synthesis and thermogenesis in response to heme by directly binding to electron transport chain complexes and SERCA2b.

Production of oxidized biomass is necessary to support cancer cell proliferation. In this work, Li et al. provide a quantitative analysis of the cellular needs and biochemical bottlenecks in lipid biosynthesis arising from the requirement to regenerate the cofactor NAD⁺.

Reductive glutamine metabolism supports cell proliferation under stress conditions such as hypoxia. Here Fendtet al.report that the ratio between the two metabolites α-ketoglutarate and citrate determines whether glutamine is metabolized oxidatively or reductively.

A method in which pooled barcoded human cancer cell lines are injected into a mouse xenograft model enables simultaneous mapping of the metastatic potential of multiple cell lines, and shows that breast cancer cells that metastasize to the brain have altered lipid metabolism.