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Tumour cells have dynamic and varied demands for nutrients that are dependent on many factors, including the nutrient availability in the tumour microenvironment, crosstalk between stromal cells and oncogenic signalling within tumour cells. The metabolic reprogramming that occurs in tumour cells allows them to survive and grow within the changeable and hostile tumour microenvironment; it can also alter epigenetic regulation and influence antitumour immune responses. The key nutrients oxygen, glutamine, serine, glucose and fatty acids are especially important for tumour cell survival and growth. Metabolic reprogramming can also lead to the production of error products that have roles in tumorigenesis and tumour progression. Therefore, metabolic changes in tumour cells can be used in clinical imaging and are being developed as targets for the treatment of patients with cancer.
The articles in this specially-commissioned Focus on Tumour metabolism tackle the metabolism of key nutrients and metabolic reprogramming that are important in tumour growth and survival, while also considering implications for the clinic.
This Foreword introduces the nine Review articles in our Focus on Tumour Metabolism and discusses the main areas of tumour metabolism for further research.
Chaeet al. show that mitochondrially-localized AKT phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) to promote tumour cell growth and survival in hypoxic conditions.
Sousaet al. demonstrate a reciprocal metabolic cross-talk between pancreatic stellate cells (PSCs) and pancreatic tumour cells whereby secreted autophagic alanine from PSCs is taken up by tumour cells and used as an alternative carbon source to support tumour growth.
Acidosis reprograms the metabolism of cancer cells toward fatty acid oxidation by downregulating acetyl-CoA carboxylase ACC2 through histone deacetylation
Mayers, Torrenceet al. show that lung tumours driven by oncogenic KRAS and loss of p53 depend on branched-chain amino acid metabolism, whereas pancreatic tumours driven by the same genetic defects do not.
Three studies demonstrate the preclinical potential of a novel class of hypoxia-inducible factor 2α (HIF2α) antagonists in the treatment of von Hippel–Lindau (pVHL)-deficient clear cell renal cell carcinoma.
Brand and colleagues show that increased tumour lactate dehydrogenase A (LDHA)-mediated lactic acid production dampens activation and cytokine production of infiltrating T and natural killer (NK) cells allowing tumours to escape immune detection and promoting tumour growth.
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.
This Review provides an overview of glutamine metabolism and its involvement in tumorigenesisin vitro and in vivo, exploring the recent potential applications of basic science discoveries in the clinical setting.
Serine supports many biosynthetic pathways, including the one-carbon cycle. This Review discusses how cancer cells acquire and use serine, and explores novel therapeutic approaches to limit serine metabolism.
The reprogramming of glucose metabolism in cancer cells, which have increased flux through glycolysis and related pathways, offers the promise of targeted inhibitors to selectively eradicate cancer cells either by themselves or as adjuvants to existing therapeutic modalities.
The availability of oxygen and nutrients changes during tumour evolution, which can have an effect on gene expression and diverse metabolic reactions as cells try to adapt to the new environment. In this Review the authors summarize how these metabolic adaptations are integrated in hypoxic tumour cells and their role in disease progression.
This Review discusses how acetate functions as a nutritional source for tumours and as a regulator of cancer cell stress, and how preventing its (re)capture by cancer cells may provide an opportunity for therapeutic intervention.
Alterations in the epigenome and metabolism bidirectionally regulate molecular rewiring in cancer cells. This Review discusses how metabolic remodelling can contribute to tumour epigenetic alterations, thereby affecting cancer cell differentiation, proliferation and/or apoptosis as well as therapeutic responses.
The mevalonate (MVA) pathway is an essential metabolic pathway that is affected by many oncogenic signalling pathways. This Review discusses the opportunity to immediately target the MVA pathway in cancer with agents approved for other therapeutic uses, such as statins.
Lipid metabolism, especially fatty acid (FA) synthesis, is essential for membrane biosynthesis, energy storage and the generation of signalling molecules. This Review explores how FA synthesis promotes tumorigenesis and tumour progression and might be targeted therapeutically.