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Ralph DeBerardinis obtained an MD and PhD from the University of Pennsylvania, then trained in Pediatrics and Medical Genetics at Children’s Hospital of Philadelphia. He moved to the University of Texas Southwestern Medical Center (UTSW) in 2008, serving as Chief of Pediatric Genetics and Metabolism from 2013 to 2024. He became an Investigator in the Howard Hughes Medical Institute in 2018 and was elected to the National Academy of Medicine in 2020. DeBerardinis’s current roles at UTSW include directing the Eugene McDermott Center for Human Growth and Development and the Genetic and Metabolic Disease Program in the Children’s Research Institute.

Chen et al. show that PEX39 cooperates with PEX7 in the peroxisomal import of proteins containing a PTS2 site and uncover an (R/K)PWE motif in PEX39 and PEX13 that binds to PEX7 and facilitates the import of PTS2-containing proteins.

In human cell lines with mutant KRAS and loss of LKB1, CPS1 expression correlates inversely with LKB1 expression; silencing CPS1 in these cells induces DNA damage and cell death as a result of pyrimidine depletion rather than ammonia toxicity.

Malignant cells are able to survive and grow in detached conditions, despite the associated increase in reactive oxygen species; here a novel metabolic pathway used by cancer cells as they adapt to anchorage-independent growth is described.

Rao and Cai et al. perform a detailed metabolic comparison between primary tumours from patients and their matching xenografts, which identify conserved as well as divergent metabolic patterns.

Somatic copy number alterations (SCNA) can confound gene co-expression analysis in cancers. Here the authors develop a method to remove the effects of SCNA in co-expression analysis, improving the analysis of network rewiring in cancer, and provide a database with adjusted data from TCGA.

Hawk et al. show that RIPK1 activation during extracellular matrix detachment induces mitophagy through mitochondrial phosphatase PGAM5 to increase reactive oxygen species and non-apoptotic cell death, and that antagonizing RIPK1/PGAM5 enhances tumour formation.

A tightly regulated enzyme balances energy production and the synthesis of macromolecules from glucose in cancer cells. Upsetting this balance by stimulating the enzyme's activity can suppress tumour growth in mice.

A tracer molecule has been used to analyse tumours in vivo in mice and to group cancers according to their metabolic characteristics. Such information could have implications for determining how different malignancies are treated.

Tumors often overexpress enzymes that synthesize fatty acids, but the requirement for fatty acid synthesis in tumor growth is unclear. A new fatty acid–synthesis inhibitor blunts lung tumor growth in mice, which implicates this process as a targetable liability.

Studying changes in the metabolic properties of kidney cancer in patients reveals an increased need for mitochondrial metabolism as tumors metastasize from the kidney to distant organs.

Lipoprotein uptake dependent on sulfated glycosaminoglycans linked to cell-surface proteoglycans is a key determinant of ferroptosis sensitivity in cancer.

Tumour cells with defective mitochondria are found to use glutamine-dependent reductive carboxylation, rather than oxidative metabolism, as the major pathway of citrate and lipid formation.

Analysis of endothelial cells, which are involved in blood-vessel formation, unexpectedly reveals that proliferation in this cell type depends on fatty-acid oxidation to support DNA synthesis. See Article p.192

Burroughs and DeBerardinis discuss the metabolic pathways that tumour cells employ to promote their survival and proliferation, and present the current approaches to study cancer metabolism in an in vivo setting.

Metabolomics analysis of the mouse embryo shows a metabolic shift towards the tricarboxylic acid cycle between gestational days 10.5 and 11.5, leading to the subsequent development of organ-specific metabolic programmes.

Tumour cells undergo oncogene-regulated metabolic reprogramming that maximizes survival and growth. However, little is known about metabolic interactions between tumour cells and their non-malignant neighbours in the stroma. Bone-marrow-derived stromal cells are now shown to provide cysteine, an essential nutrient that enables leukaemia cells to resist oxidative stress.

Differences in MCT1 function among melanoma cells confer differences in oxidative stress resistance and metastatic potential.

Inborn errors of metabolism are inherited monogenic disorders caused by mutations in genes encoding metabolic enzymes that can result in malignancy. This Opinion article discusses how studying these rare diseases might provide insight into how specific metabolic changes contribute to cancer initiation, development, diagnosis and treatment.

A particularly aggressive subtype of lung cancer with mutations in KRAS and LKB1 is shown to depend on increased hexosamine biosynthesis mediated by the enzyme GFPT2.

Metabolic dysregulation in the development of clear cell renal cell carcinoma (ccRCC) remains to be understood. Here the authors identify that a carnitine synthesis enzyme BBOX1, which inhibits TBK1-mTORC1 signaling and glycolysis, is often lost in ccRCC.

Amino acids availability is normally a limitation for protein synthesis and can determine cancer progression and therapy response. Here, the authors show that MYC-associated cancer has a dependency on tryptophan not because of translation regulation, but Indole 3-Pyruvate synthesis.

This Case Study describes the management of a patient with a fumarate hydratase (FH)-deficient type-2 papillary renal cell carcinoma. On the basis of results fromin vitro experiments, the authors decided to treat the patient with the glycolytic inhibitor 2DG (2-deoxy-D-glucose), a new anticancer drug that is currently in clinical development.

Hydronium ions bordering cancer cells are highly concentrated into a small extracellular region, and in tumour tissue such severely polarized acidity correlates with the expression of monocarboxylate transporters and with the exclusion of cytotoxic T cells.

Polycystic kidney disease (PKD) is characterized by the formation of large fluid-filled cysts. Here Flowers and colleagues show that loss of Lkb1, downregulated in PKD, renders kidney cells dependent on glutamine for growth, and suggest that inhibition of glutamine metabolism may prevent cyst development in PKD.

Although tumour metabolism is well recognized as a key feature in cancer initiation and progression, little is known about metabolic reprogramming in patients. In this Review, Bartman et al. discuss stable-isotope tracing as a means to probe tumour metabolism in vivo and provide an overview of isotope labelling studies performed in patients with cancer.

Wei et al. show that proteolytic cleavage of fatty acid synthase (FASN) upon stress contributes to stress resolution. This role in stress resolution of the resulting C-terminal fragment of FASN is independent of its canonical function in fatty acid synthesis.

Malladi and colleagues show that inhibiting DRP1 limits mitochondrial plasticity, resulting in increased mitochondrial fusion, impaired fatty acid oxidation and reduced metastasis formation in breast cancer models.

We are approaching the 100th anniversary of Otto Warburg’s first description of the metabolic phenotype bearing his name—a propensity for tumours to metabolize glucose anaerobically rather than aerobically, even when oxygen is available. Generations of scientists have studied the Warburg effect, yet misconceptions persist about its causes and relationship to oxidative metabolism in the mitochondria. Here, we review the definition of the Warburg effect and discuss its place within a modern understanding of cancer biology.

Here Mukherjee et al. characterize the bidirectional communication between adipose tissue and ovarian cancer cells and show that adipocytes instruct cancer cells to divert glycolytic glycerol-3-phosphate towards lipid synthesis, thus promoting metastasis.

In this study, Patrick et al. provide insight into the regulation of branched-chain amino acid metabolism and its impact on whole-body physiology by identifying and characterizing a metabolon formation.

Glycolysis in normal epithelial cells responds to microenvironmental mechanics via the modulation of actin bundles that sequester the phosphofructokinase-targeting ubiquitin ligase TRIM21, a process superseded by persistent actin bundles in cancer cells.

Cellular metabolism is altered in many cancer types and the advent of metabolomics has allowed us to understand more about how this is dysregulated. Here, the authors report a method named CARVE to analyse the arterial supply and venous drainage of glioma patients during surgery and identify the metabolites that may be consumed and produced by the cancer.

The cap-binding protein eIF4E is a master regulator of mRNA translation. Conn et al. identify a specific subset of mRNAs governing lipid metabolism and storage that require eIF4E for translation in the liver during obesity.

Ascorbate depletion in mice increased haematopoietic stem-cell frequency and promoted leukaemogenesis, partly by reducing the function of the Tet2 tumour suppressor enzyme.

Chen and colleagues report that the third enzyme in the oxidative pentose phosphate pathway (PPP), 6PGD, controls cancer cell proliferation by regulating LKB1–AMPK signalling. Inhibitors of 6PGD decrease tumorigenesis in mouse xenografts.

NADPH exists in separate cellular pools within the cytosol and mitochondria. Tran et al. find that mitochondrial NADPH is essential to enable proline biosynthesis during cell growth.

Keratinocytes require glucose for injury- or inflammation-driven but not homeostatic proliferation, and glucose-transport blockade blocks psoriasis-like pathology in experimental models.

Treatment responses of melanoma patients to MAPK pathway inhibitors are often limited. Here, the authors show that combining cardiac glycosides with MAPK inhibitors improves tumor regression by inducing intracellular acidification, mitochondrial calcium dysregulation, ATP depletion, and cell death.

Kofuji et al. demonstrate that upregulation of IMPDH2 promotes nucleostemin stabilization and nucleoli malformation, and its inactivation induces growth arrest in glioblastoma.

The imaging of tumours is challenging because of the wide range of different cancers. Now, the rapid detection of tumours, independent of type, is achieved using a nonlinear amplification strategy that employs ultrasensitive pH-responsive fluorescent nanoparticles that illuminate within tumour neovasculature or in response to the tumour’s acidic extracellular environment.

Human melanoma cells grown in mice experience high levels of oxidative stress in the bloodstream such that few metastasizing cells survive to form tumours; the rare melanoma cells that successfully metastasize undergo metabolic changes that increase their capacity to withstand this stress, and antioxidant treatments increase metastasis formation by human melanoma cells, while inhibiting antioxidant pathways had the reverse effect.