Metabolic regulation of ferroptosis in the tumor microenvironment

Mbah, Nneka E.; Lyssiotis, Costas A.

doi:10.1016/j.jbc.2022.101617

Cited by 54 publications

(39 citation statements)

References 145 publications

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“…Several recent studies have illustrated that the mesenchymal state of cancer cells exposes a vulnerability to ferroptosis - a form of metabolic-stress cell death induced by inhibiting the GPX4 lipid peroxidase pathway 34, 35 . Ferroptosis can be induced by genetic or pharmacological manipulations that impair cystine uptake, block glutathione (GSH) synthesis, or directly inhibit activity of the central lipid peroxidase, GPX4 36 ( Figure 3B ). Based on this knowledge, we hypothesized that DGC, owing to its high mesenchymal gene signature, would be susceptible to GPX4 inhibition and ferroptosis.…”

Section: Resultsmentioning

confidence: 99%

Therapeutic targeting of differentiation state-dependent metabolic vulnerabilities in DIPG

Mbah

Myers

Chung

et al. 2022

Preprint

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H3K27M diffuse intrinsic pontine gliomas (DIPG) exhibit cellular heterogeneity comprising less-differentiated, stem-like glioma cells that resemble oligodendrocyte precursors (OPC) and more differentiated astrocyte (AC)-like cells. H3K27M DIPG stem-like cells exhibit tumor-seeding capabilities in vivo, a feature lost or greatly diminished in the more differentiated AC-like cells. In this study, we established isogenic in vitro models of DIPG that closely recapitulated the OPC-like and AC-like phenotypes of DIPG cells. Using these tools, we performed transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs operative in the different cellular states. From this, we defined new strategies to selectively target metabolic vulnerabilities within the specific tumor populations. Namely, we showed that the AC-like cells exhibited a more mesenchymal phenotype and were thus sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulated cholesterol metabolism and mitochondrial oxidative phosphorylation (OXPHOS) and were accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors showed efficacy and extended survival in preclinical orthotopic models established with stem-like H3K27M DIPG cells. Together, this study demonstrates that cellular subtypes within DIPGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain.

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Section: Resultsmentioning

confidence: 99%

Therapeutic targeting of differentiation state-dependent metabolic vulnerabilities in DIPG

Mbah

Myers

Chung

et al. 2022

Preprint

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“…This lipid dependency of FLT3 -mutant AML was further observed at the single cell level in vivo in PDX assays, highlighting the link between SCD, lipid peroxidation, ferroptosis priming and post-FLT3i residual disease in vivo . In same vein, acyl-CoA dehydrogenase involved into FA metabolism protects glioblastoma cells from toxic lipid oxidation, which favors their adaptive resistance to drug-induced stress 61,62 . Together, C/EBPα may account for the high reliance of leukemic cells on sustained FA catabolic or anabolic pathways.…”

Section: Discussionmentioning

confidence: 99%

C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

Sabatier

Birsen

Tamburini

et al. 2022

Preprint

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While transcription factor C/AAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress. Moreover, this C/EBPα-dependent adaptation of FA homeostasis was exploited by combining FLT3 and glutathione peroxidase 4 (GPX4) inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML with promising therapeutic application

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“…A common issue is that translating anti-cancer strategies to the clinical setting may be limited due to the heterogeneity and improved complexity of human cancers in comparison to animal models. In addition, conditions in culture are often non-physiologic, as the behavior and properties of cancer cells in tumors, as well as ferroptosis susceptibility, are influenced by multiple factors, including their in vivo microenvironment [243].…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma

Kusnick

Bruneau

Tacke

et al. 2022

Immuno

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Ferroptosis is a recently recognized iron-dependent form of non-apoptotic regulated cell death (RCD) characterized by lipid peroxide accumulation to lethal levels. Cancer cells, which show an increased iron dependency to enable rapid growth, seem vulnerable to ferroptosis. There is also increasing evidence that ferroptosis might be immunogenic and therefore could synergize with immunotherapies. Hepatocellular carcinoma (HCC) is the most common primary liver tumor with a low survival rate due to frequent recurrence and limited efficacy of conventional chemotherapies, illustrating the urgent need for novel drug approaches or combinatorial strategies. Immunotherapy is a new treatment approach for advanced HCC patients. In this setting, ferroptosis inducers may have substantial clinical potential. However, there are still many questions to answer before the mystery of ferroptosis is fully unveiled. This review discusses the existing studies and our current understanding regarding the molecular mechanisms of ferroptosis with the goal of enhancing response to immunotherapy of liver cancer. In addition, challenges and opportunities in clinical applications of potential candidates for ferroptosis-driven therapeutic strategies will be summarized. Unraveling the role of ferroptosis in the immune response could benefit the development of promising anti-cancer therapies that overcome drug resistance and prevent tumor metastasis.

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Metabolic regulation of ferroptosis in the tumor microenvironment

Cited by 54 publications

References 145 publications

Therapeutic targeting of differentiation state-dependent metabolic vulnerabilities in DIPG

Therapeutic targeting of differentiation state-dependent metabolic vulnerabilities in DIPG

C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma

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