A continuous ferroptosis-to-apoptosis landscape identifies ferroptosis biomarkers and repressors for cancer therapy
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PROVIDER: PRJNA985458 | ENA |
REPOSITORIES: ENA
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Project description:Ferroptosis, a cell death pathway driven by lipid peroxidation, is implicated in several human diseases including cancer. Although ferroptosis is entwined with apoptosis, it currently has no characteristic biomarkers or gene signature. In this project we established a continuous phenotypic gradient between ferroptosis and apoptosis and coupled it to transcriptomic and metabolomic landscapes. Omics and mechanistic studies revealed that ferroptosis was associated with enhanced MITF activity, lysosomal function, glutaminolysis, TCA cycle, and activation of ATF4, while its transition into apoptosis was attributed to enhanced ER-stress, ATF4/CHOP switch and PE/PC metabolic shift. The gradual ferroptosis-to-apoptosis transcriptomic landscape was used to generate a unique, unbiased transcriptomic predictor, the Gradient Gene Set (GGS), which classified ferroptosis and apoptosis with high accuracy. Further GGS optimization and datasets analysis of various ferroptotic and apoptotic responses revealed highly specific ferroptosis biomarkers, which were robustly validated in vitro and in vivo. A subset of the GGS was correlated with poor prognosis in breast cancer patients and in PDX models and was found to consist of different ferroptosis repressors, including PDAP1, whose knockdown suppressed breast tumor growth in a mouse model. Collectively, this study highlights molecular switches between ferroptosis and apoptosis, uncovering a highly prognostic predictive ferroptosis gene signature, pointing to a few ferroptosis repressors for targeted breast cancer therapy.
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Project description:Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle. This metabolic reprogramming was linked with reduced expression of p53-dependent genes that mediate apoptosis and ferroptosis, which preserved cell viability in response to lipotoxicity. Mechanistically, impaired mitochondrial metabolism reduced acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis, while redox drivers of ferroptosis were also reduced. Overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice enhanced oxidative capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of the oxidative state of skeletal muscle, and that this metabolic reprogramming, considered deleterious for normal metabolism, is critical to preserve muscle integrity in response to lipotoxicity.
2022-10-11 | GSE215185 | GEO
Project description:Colorectal cancer (CRC) is the third most common cancer in the world and the second leading cause of cancer-related deaths. However, there are few effective therapeutic targets for colorectal cancer. Here, we report that Capping Actin Protein, Gelsolin Like (CAPG), a protein involved in actin related movement, is significantly overexpressed in human CRC tissues, and that expression levels are inversely correlated with overall survival. CAPG knockdown CRC cell lines inhibited cell proliferation, blocked cell cycle in G1 phase, increased apoptosis rate and promoted the occurrence of ferroptosis. RNA-seq data suggested that CAPG silencing promotes cell cycle arrest, apoptosis, and ferroptosis by activating the P53 pathway. Therefore, CAPG has potential to serve as a prognostic marker as well as a cancer therapy target in the future.
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Project description:The formation of extracellular vesicles (EVs) has emerged as a novel paradigm in cell-to-cell communication during health and disease. According to the type of cell death modalities, the intercellular functions of EVs may be influenced by their biogenesis and composition. To identify a possible EV cargo signature, we performed a comparative analysis of steady-state (ssEVs) and cell death-associated EVs (cdEVs) following apoptosis (apoEVs), necroptosis (necEVs) and ferroptosis (ferEVs) in the same cell type. We determined the physical and biochemical characteristics, the protein cargo by mass spectrometry.
2023-10-12 | PXD039297 | Pride
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Project description:Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, is characterized by an aggressive clinical course. In approximately one-third of DLBCL patients, first-line multi-agent immunochemotherapy fails to produce a durable response. Molecular heterogeneity and apoptosis resistance pose major therapeutic challenges in DLBCL treatment. To circumvent apoptosis resistance, the induction of ferroptosis might represent a promising strategy for lymphoma therapy. Here, a compound library targeting epigenetic modulators was screened to identify ferroptosis-sensitizing drugs. Strikingly, bromodomain and extra-terminal domain (BET) inhibitors sensitized cells of the germinal center B cell-like (GCB) subtype of DLBCL to ferroptosis induction and the combination of BET inhibitors with ferroptosis inducers, such as dimethyl fumarate (DMF) or RSL3, synergized in the killing of DLBCL cells in vitro and in vivo. On the molecular level, the BET protein BRD4 was found to be an essential regulator of ferroptosis suppressor protein 1 (FSP1) expression and to thus protect GCB DLBCL cells from ferroptosis. Collectively, we identified and characterized BRD4 as an important player in ferroptosis suppression in GCB DLBCL and provide a rationale for the combination of BET inhibitors with ferroptosis-inducing agents as a novel therapeutic approach for DLBCL treatment.
2023-08-01 | GSE231871 | GEO
Project description:CD8+ T cells activated by cancer immunotherapy execute tumor clearance mainly by inducing cell death through perforin-granzyme- and Fas/Fas ligand-pathways. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent lipid peroxide accumulation. Although it was mechanistically illuminated in vitro, emerging evidence has shown that ferroptosis may be implicated in a variety of pathological scenarios. However, the involvement of ferroptosis in T cell immunity and cancer immunotherapy is unknown. Here, we find that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumor cells, and in turn, increased ferroptosis contributes to the anti-tumor efficacy of immunotherapy. Mechanistically, IFNg released from CD8+ T cells downregulates expression of SLC3A2 and SLC7A11, two subunits of glutamate-cystine antiporter system xc-, restrains tumor cell cystine uptake, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis. In preclinical models, depletion of cyst(e)ine by cyst(e)inase in combination with checkpoint blockade synergistically enhances T cell-mediated anti-tumor immunity and induces tumor cell ferroptosis. Thus, T cell-promoted tumor ferroptosis is a novel anti-tumor mechanism. Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade.
2019-03-16 | GSE128392 | GEO
Project description:Ferroptosis is a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. The development of the concept of ferroptosis stemmed from an active search for alternatives to apoptosis in cancer cells. Ferroptosis inducers have shown remarkable effectiveness in killing tumor cells in vitro, yet with no obvious success in experimental animal models, with a notable exception of immune-deficient mice 1,2. This suggests the potential poorly understood contribution of ferroptosis on immune cells. Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of anti-tumor immunity3-5. Here, we found that PMN-MDSC in the tumor microenvironment (TME), spontaneously die by ferroptosis. While decreasing the presence of PMN-MDSC, ferroptosis induces the release of oxygenated lipids and limits mouse and human T cell activity. In immune-competent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSC, reduces tumor progression, and synergizes with immune checkpoint blockade (ICB) to suppress the tumor growth. In contrast, induction of ferroptosis in immune-competent mice promotes tumor growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to limit tumor progression.
2022-09-19 | GSE205371 | GEO
Project description:Ferroptosis is a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. The development of the concept of ferroptosis stemmed from an active search for alternatives to apoptosis in cancer cells. Ferroptosis inducers have shown remarkable effectiveness in killing tumor cells in vitro, yet with no obvious success in experimental animal models, with a notable exception of immune-deficient mice 1,2. This suggests the potential poorly understood contribution of ferroptosis on immune cells. Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of anti-tumor immunity3-5. Here, we found that PMN-MDSC in the tumor microenvironment (TME), spontaneously die by ferroptosis. While decreasing the presence of PMN-MDSC, ferroptosis induces the release of oxygenated lipids and limits mouse and human T cell activity. In immune-competent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSC, reduces tumor progression, and synergizes with immune checkpoint blockade (ICB) to suppress the tumor growth. In contrast, induction of ferroptosis in immune-competent mice promotes tumor growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to limit tumor progression.
2022-09-24 | GSE213861 | GEO