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Review
. 2024 Oct 4;10(40):eadq7305.
doi: 10.1126/sciadv.adq7305. Epub 2024 Oct 2.

Identifying metabolic limitations in the tumor microenvironment

Guillaume Cognet  1 , Alexander Muir  1
Affiliations
Review

Identifying metabolic limitations in the tumor microenvironment

Guillaume Cognet et al. Sci Adv. .

Abstract

Solid tumors are characterized by dysfunctional vasculature that limits perfusion and delivery of nutrients to the tumor microenvironment. Limited perfusion coupled with the high metabolic demand of growing tumors has led to the hypothesis that many tumors experience metabolic stress driven by limited availability of nutrients such as glucose, oxygen, and amino acids in the tumor. Such metabolic stress has important implications for the biology of cells in the microenvironment, affecting both disease progression and response to therapies. Recently, techniques have been developed to identify limiting nutrients and resulting metabolic stresses in solid tumors. These techniques have greatly expanded our understanding of the metabolic limitations in tumors. This review will discuss these experimental tools and the emerging picture of metabolic limitations in tumors arising from recent studies using these approaches.

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Figures

Fig. 1.
Fig. 1.. Tools to identify metabolic limitations in tumors.
(A) Interstitial fluid can be isolated from tumors and analyzed using mass spectrometry to characterize nutrient concentrations in the tumor microenvironment. These nutrient concentrations can then be compared to known transport or cellular affinities for nutrients to infer the nutrients limiting cellular metabolism in the tumor microenvironment. (B) The development of CRISPR-activation libraries enables rapid screening of the transporters whose overexpression improves the fitness of cancer cells in the tumor microenvironment. Given that transporter overexpression provides a strong fitness advantage to cancer cells experiencing limitation of the cognate nutrient, such screens can identify which nutrients are limiting in the microenvironment. (C) The analysis of the codons engaged by ribosomes in tumors can identify which amino acids are limited and slow translation in a tumor. If an amino acid is limited in the tumor microenvironment, then ribosomes will increasingly stall at these amino acid codons. This approach has been used to identify amino acids limitations in human and animal tumors. Created with BioRender.com.
See this image and copyright information in PMC

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