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Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment

Nature Reviews Cancer volume 21, pages 510–525 (2021)Cite this article

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Abstract

Oncogenic mutations in KRAS drive common metabolic programmes that facilitate tumour survival, growth and immune evasion in colorectal carcinoma, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. However, the impacts of mutant KRAS signalling on malignant cell programmes and tumour properties are also dictated by tumour suppressor losses and physiological features specific to the cell and tissue of origin. Here we review convergent and disparate metabolic networks regulated by oncogenic mutant KRAS in colon, lung and pancreas tumours, with an emphasis on co-occurring mutations and the role of the tumour microenvironment. Furthermore, we explore how these networks can be exploited for therapeutic gain.

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Fig. 1: KRAS* rewires cancer cell metabolism.
Fig. 2: KRAS* synergizes with co-occurring mutations to direct metabolism.
Fig. 3: Tissue specific metabolism hijacked by KRAS*.
Fig. 4: Interactions in the KRAS* TME.

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Acknowledgements

S.A.K. is supported by NIH award F31CA247457. T.P. is supported by NIH grants R37CA222504 and R01CA227649 and American Cancer Society Research Scholar Grant RSG-17-200-01—TBE. Y.M.S. is supported by NIH grants R01CA245546 and R01CA148828. C.A.L. is supported by NIH grants R37CA237421, R01CA248160 and R01CA244931.

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Authors and Affiliations

  1. Doctoral Program in Cancer Biology, University of Michigan Medical School, Ann Arbor, MI, USA

    Samuel A. Kerk

  2. Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA

    Samuel A. Kerk, Yatrik M. Shah & Costas A. Lyssiotis

  3. Department of Pathology, New York University School of Medicine, New York, NY, USA

    Thales Papagiannakopoulos

  4. Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA

    Thales Papagiannakopoulos

  5. Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

    Yatrik M. Shah & Costas A. Lyssiotis

  6. Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA

    Yatrik M. Shah & Costas A. Lyssiotis

Authors
  1. Samuel A. Kerk
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  2. Thales Papagiannakopoulos
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  3. Yatrik M. Shah
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  4. Costas A. Lyssiotis
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Costas A. Lyssiotis.

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Competing interests

T.P. has received honoraria and consulting fees from Calithera Biosciences and research support from Dracen Pharmaceuticals and Agios Pharmaceuticals. C.A.L. has received consulting fees from Astellas Pharmaceuticals and is an inventor on patents pertaining to KRAS-regulated metabolic pathways, redox control pathways in pancreatic cancer and targeting the GOT1 pathway as a therapeutic approach. Y.M.S. and S.A.K. have no competing interests to declare.

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Glossary

Glycolysis

The enzymatic oxidation of glucose to pyruvate, which produces energy and carbon for bioenergetic and biosynthetic processes.

Oxidation state

In cellular metabolism, the availability of electron acceptors as determined by the breakdown or production of metabolites.

Mitophagy

Selective targeting and degradation of mitochondria, often those that are defective or excessive.

Electron transport chain

(ETC). A series of electron-accepting enzymes embedded in the inner mitochondrial membrane responsible for producing the proton-motive force needed for energy production.

Reactive oxygen species

(ROS). Small, oxygen-containing molecules that are highly reactive due to the electron-accepting nature of oxygen.

Mitochondrial fission or mitochondrial fusion

A process by which mitochondria are combined (fusion) or divided into smaller fragments (fission).

Glutaminolysis

The enzymatic breakdown of the amino acid glutamine.

Tricarboxylic acid (TCA) cycle

A series of mitochondrial enzymatic reactions that oxidize metabolic intermediates to produce reducing equivalents that drive the electron transport chain and intermediates for the synthesis of lipids and amino acids.

Anaplerosis

Replenishment of tricarboxylic acid cycle intermediates.

Macropinocytosis

Regulated, non-specific engulfment of the extracellular space by the cellular plasma membrane to obtain nutrients.

Autophagy

Degradation of intracellular metabolites and organelles to eliminate damaged cellular components and/or provide basic metabolic building blocks.

Urea cycle

A series of chemical reactions involving nitrogen-containing metabolites essential for recycling nitrogen or excreting toxic ammonia waste as urea.

Glutathione

(GSH). Cellular antioxidant composed of glutamate, cysteine and glycine important for quenching damaging reactive oxygen species levels.

Cystine

The water-soluble dimer of the amino acid cysteine.

System XC −

Amino acid antiporter system that exchanges glutamate for cystine.

Oxidative phosphorylation

Oxygen-dependent process by which the proton-motive force between the inner mitochondrial membrane space and matrix is used to generate ATP.

Hypoxia-inducible factors

(HIFs). Transcription factors, stabilized under conditions of low oxygen levels, targeting the promoters of genes containing hypoxia response elements.

Ferroptosis

An oxidative, iron-dependent form of programmed cell death.

Isotope tracing

Application of metabolites in which stable isotopes are incorporated to follow the metabolism or fate of a given nutrient (for example via mass spectroscopy-based metabolomics).

Acinar–ductal metaplasia

The morphological and transcriptional programmes by which acinar cells dedifferentiate into ductal cells in response to injury or oncogenic stress.

Pyrimidine synthesis

The metabolic pathway producing the nucleotides uridine, cytidine and thymidine.

Microsatellite instability

(MSI). An inherent propensity for genomic mutations caused by malfunctioning DNA repair machinery.

Deamidases

Enzymes that catalyse the removal of amido groups.

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Kerk, S.A., Papagiannakopoulos, T., Shah, Y.M. et al. Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment. Nat Rev Cancer 21, 510–525 (2021). https://doi.org/10.1038/s41568-021-00375-9

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