Publications by authors named "Guillaume Cognet"
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.
View Article and Find Full Text PDFUnlabelled: Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival.
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- The study explores the role of the transcription factor CCAAT-enhancer binding protein α (C/EBPα) in lipid metabolism and cellular homeostasis in acute myeloid leukemia (AML), particularly with mutations in FLT3.
- Researchers found that C/EBPα and FLT3 activation enhance lipid production and desaturation in AML cells, leading to increased vulnerability to oxidative stress.
- Inhibiting C/EBPα or FLT3 demonstrates potential for therapeutic strategies targeting lipid metabolism to promote ferroptotic cell death in FLT3-mutant AML, a type of leukemia affecting 30% of patients.
Article Synopsis
- Therapy resistance is a big issue in treating acute myeloid leukemia (AML), and researchers have created a 'MitoScore' to identify patients with high oxidative phosphorylation in their cells.
- AML cells that resist treatment with cytarabine (AraC) show reliance on certain mitochondrial proteins and respond well to a combination of venetoclax (VEN) and AraC, but not to VEN with azacytidine.
- Further research found that resistant AML cells adapt by altering their mitochondrial functions, and targeting these adaptations could improve treatment outcomes, suggesting a potential strategy to alternate between VEN therapies based on MitoScore levels to boost effectiveness.
Article Synopsis
- * IDH mutations found in preleukemic stem cells are stable at relapse, suggesting that targeting these cells could help achieve long-term remission in AML patients with IDH mutations.
- * Research indicates that the oncometabolite (R)-2-HG produced by IDH mutant enzymes activates vitamin D receptor pathways, enhancing the differentiation of AML cells when treated with ATRA and/or vitamin D, offering a new therapeutic strategy for these patients.
Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells.
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