Tumour initiation and progression requires the metabolic reprogramming of cancer cells. Cancer cells autonomously alter their flux through various metabolic pathways in order to meet the increased bioenergetic and biosynthetic demand as well as mitigate oxidative stress required for cancer cell proliferation and survival. Cancer driver mutations coupled with environmental nutrient availability control flux through these metabolic pathways. Metabolites, when aberrantly accumulated, can also promote tumorigenesis. The development and application of new technologies over the last few decades has not only revealed the heterogeneity and plasticity of tumours but also allowed us to uncover new metabolic pathways involved in supporting tumour growth. The tumour microenvironment (TME), which can be depleted of certain nutrients, forces cancer cells to adapt by inducing nutrient scavenging mechanisms to sustain cancer cell proliferation. There is growing appreciation that the metabolism of cell types other than cancer cells within the TME, including endothelial cells, fibroblasts and immune cells, can modulate tumour progression. Because metastases are a major cause of death of patients with cancer, efforts are underway to understand how metabolism is harnessed by metastatic cells. Additionally, there is a new interest in exploiting cancer genetic analysis for patient stratification and/or dietary interventions in combination with therapies that target metabolism. In this Perspective, we highlight these main themes that are currently under investigation in the context of in vivo tumour metabolism, specifically emphasizing questions that remain unanswered.
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The authors are grateful to R. Deberardinis (UT Southwestern) for helpful and insightful comments. They thank L. Diebold and C. Reczek from the Chandel laboratory for their helpful input and editing. This work was funded by National Institutes of Health (NIH) Grant 5R35CA197532. We have largely confined the references to the past few years with the emphasis on in vivo findings in the field and have cited many excellent references in the past year.
N.S.C. is on the scientific advisory board of Rafael Pharmaceuticals and Penrose TherapeuTx. I.M.-R. declares no competing interests.
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A highly regulated process through which proteins and organelles are delivered to the lysosome and degraded.
A distinct form of programmed cell death that requires reactive oxygen species (ROS) and iron accumulation to cause lethal lipid peroxidation.
An enzyme that degrades hyaluronic acid into monosaccharides.
- Peroxiredoxin enzymes
Cysteine-dependent peroxidases that convert hydrogen peroxide (H2O2) to water.
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Martínez-Reyes, I., Chandel, N.S. Cancer metabolism: looking forward. Nat Rev Cancer (2021). https://doi.org/10.1038/s41568-021-00378-6