Metabolic reprogramming of hypoxic tumor-associated macrophages through CSF-1R targeting favors treatment efficiency in colorectal cancers
Khaldoun Gharzeddine, Cristina Gonzalez Prieto, Marie Malier, Clara Hennot, Renata Grespan, Yoshiki Yamaryo‐Botté, Cyrille Y. Botté, Fabienne Thomas, Marie‐Hélène Laverrière, Édouard Girard, Gaël S. Roth, Arnaud Millet
Abstract
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.