Metabolic reprogramming of hypoxic tumour-associated macrophages through CSF-1R targeting favours treatment efficiency in colorectal cancers
Gharzeddine, K.; Gonzales Pietro, C.; Malier, M.; Hennot, C.; Grespan, R.; Yamaryo, Y.; Botte, C.; Thomas, F.; Laverriere, M. H.; Girard, E.; Roth, G.; MILLET, A.
Show abstract
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, blockade of the CSF-1R receptor is one of the most promising one. Here, we characterize the resulting state of human macrophages exposed to a CSF-1R kinase inhibitor. 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 SREBP2, a transcription factor that controls cholesterol and fatty acid synthesis. We also show that the inhibition of ERK1/2 phosphorylation resulting from targeting the CSF-1R receptor destabilizes the expression of HIF2 in hypoxia resulting in the downregulation of dihydropyrimidine dehydrogenase expression restoring the sensitivity to 5-fluorouracil in colorectal cancer. These results reveal the unexpected metabolic rewiring resulting from the CSF-1R receptor targeting of human macrophages in tumors.
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