Biology subjects

MILLET, A.

Publications and source records attributed to MILLET, A..

4 recordsLinked to original sources

bioRxiv2024

Spatial organization of mediated-macrophage chemoprotective niches in solid tumors: A mathematical analysis

Acquired resistance is one of the major causes of failure of standard therapies in cancer patients. Chemotherapeutic agents are still widely used and the understanding of the mechanisms leading to secondary resistance to these molecules are still puzzling. Recently, the role of the tumor immune microenvironment has been recognized. Among the cells potentially involved, macrophages seem to be the perfect culprits. In a previous work, we have shown that hypoxic macrophages are able to provide strong protection against 5-fluorouracil, a first-line chemotherapeutic agent in digestive cancers. In the present work, we use mathematical modeling to explore the spatiotemporal aspects of the treatment-induced organization of the tumor environment. Based on analytical and numerical analysis, we propose that macrophage-driven protection against chemotherapy under treatment does not rely solely on biochemical degradation, but is enhanced by the emergence of spatially structured chemotherapeutic protective niches. This work paves the way for the development of new therapeutic strategies that rely on targeting the spatial organization of tumors as a way to control treatment resistance.

systems biology↗

bioRxiv2024

Tumor-associated macrophages confer resistance to chemotherapy (Trifluridine/Tipiracil) in digestive cancers by overexpressing Thymidine Phosphorylase

Pyrimidine analogs are part of the first-line chemotherapy regimen for gastrointestinal cancers. Trifluridine combined with tipiracil, a specific thymidine phosphorylase inhibitor, in TAS-102 has recently emerged as a potential alternative in the face of primary or secondary chemoresistance to 5-fluorouracil. Despite its promise, in the current study, we report that macrophage-specific overexpression of thymidine phosphorylase results in macrophage-induced chemoresistance to TAS-102 that is insensitive to tipiracil inhibition. In addition, we demonstrate the human specificity of this mechanism, as mouse macrophages do not express significant levels of thymidine phosphorylase. To study the importance of macrophages in chemoresistance to trifluridine, we developed a humanized mouse model with tumor-implanted human macrophages and demonstrated their important role in treatment resistance to pyrimidine analogs. We also showed in human colorectal cancer that macrophages represent a major source of thymidine phosphorylase expression leading to chemoresistance. SignificanceThymidine phosphorylase overexpression in TAMs confers chemoresistance to TAS-102 in digestive cancers.

pathology↗

bioRxiv2024

Metabolic reprogramming of hypoxic tumour-associated macrophages through CSF-1R targeting favours treatment efficiency in colorectal cancers

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.

immunology↗

bioRxiv2020

Hypoxia Drives Dihydropyrimidine Dehydrogenase Expression in Macrophages and Confers Chemoresistance in Colorectal Cancer

Colon adenocarcinoma is characterized by an infiltration of tumor-associated macrophages (TAMs). TAMs are associated with a chemoresistance to 5-Fluorouracil (5-FU), but the mechanisms involved are still poorly understood. In the present study, we found that macrophages specifically overexpress dihydropyrimidine dehydrogenase (DPD) in hypoxia, leading to a macrophage-induced chemoresistance to 5-FU by inactivation of the drug. Macrophage DPD expression in hypoxia is translationally controlled by the cap-dependent protein synthesis complex eIF4FHypoxic, which includes HIF-2. We discovered that TAMs constitute the main contributors to DPD activity in human colorectal primary or secondary tumors where cancer cells do not express significant levels of DPD. Together, these findings shed light on the role of TAMs in forming chemoresistance in colorectal cancers and offer the identification of new therapeutic targets. Additionally, we report that, contrary to what is found in humans, macrophages in mice do not express DPD.

cell biology↗