Metabolic reprogramming of hypoxic tumor-associated macrophages through CSF-1R targeting favors treatment efficiency in colorectal cancers
Background Tumor-associated macrophages participate in the complex network of support that favors tumor growth. Among the various strategies that have been developed to target these cells, the blockade of the colony-stimulating factor 1 receptor (CSF-1R) receptor is one of the most promising ones. H...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2024-09-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/9/e009602.full |
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| Summary: | Background Tumor-associated macrophages participate in the complex network of support that favors tumor growth. Among the various strategies that have been developed to target these cells, the blockade of the colony-stimulating factor 1 receptor (CSF-1R) receptor is one of the most promising ones. Here, we characterize the resulting state of human macrophages exposed to a CSF-1R kinase inhibitor.Methods Using RNA sequencing and metabolomics approach, we characterize the reprogramming of human monocyte-derived macrophages under CSF-1R targeting.Results We find that CSF-1R receptor inhibition in human macrophages is able to impair cholesterol synthesis, fatty acid metabolism and hypoxia-driven expression of dihydropyrimidine dehydrogenase, an enzyme responsible for the 5-fluorouracil macrophage-mediated chemoresistance. We show that this inhibition of the CSF-1R receptor leads to a downregulation of the expression of sterol regulatory element-binding protein 2, a transcription factor that controls cholesterol and fatty acid synthesis. We also show that the inhibition of extracellular signal-regulated kinase 1/2 phosphorylation resulting from targeting the CSF-1R receptor destabilizes the expression of hypoxic induced factor 2 alpha in hypoxia resulting in the downregulation of dihydropyrimidine dehydrogenase expression restoring the sensitivity to 5-fluorouracil in colorectal cancer.Conclusions These results reveal the unexpected metabolic rewiring resulting from the CSF-1R receptor targeting of human macrophages and its potential to reverse macrophage-mediated chemoresistance in colorectal tumors. |
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| ISSN: | 2051-1426 |