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    • Programming a Ferroptosis‐to‐Apoptosis Transition Landscape Revealed Ferroptosis Biomarkers and Repressors for Cancer Therapy

    Yaron Vinik, Avi Maimon,Vinay Dubey,Harsha Raj,Ifat Abramovitch,Sergey Malitsky,Maxim Itkin,Avi Ma'ayan,Frank Westermann,Eyal Gottlieb,Eytan Ruppin,Sima Lev

    Advanced science (Weinheim, Baden-Wurttemberg, Germany)（2024）

    Weizmann Inst Sci | Technion Israel Inst Technol | Icahn Sch Med Mt Sinai | German Canc Res Ctr | NCI

    Cited 2|Views30
    Abstract
    Abstract Ferroptosis and apoptosis are key cell‐death pathways implicated in several human diseases including cancer. Ferroptosis is driven by iron‐dependent lipid peroxidation and currently has no characteristic biomarkers or gene signatures. Here a continuous phenotypic gradient between ferroptosis and apoptosis coupled to transcriptomic and metabolomic landscapes is established. The gradual ferroptosis‐to‐apoptosis transcriptomic landscape is used to generate a unique, unbiased transcriptomic predictor, the Gradient Gene Set (GGS), which classified ferroptosis and apoptosis with high accuracy. Further GGS optimization using multiple ferroptotic and apoptotic datasets revealed highly specific ferroptosis biomarkers, which are robustly validated in vitro and in vivo. A subset of the GGS is associated with poor prognosis in breast cancer patients and PDXs and contains different ferroptosis repressors. Depletion of one representative, PDGFA‐assaociated protein 1(PDAP1), is found to suppress basal‐like breast tumor growth in a mouse model. Omics and mechanistic studies revealed that ferroptosis is associated with enhanced lysosomal function, glutaminolysis, and the tricarboxylic acid (TCA) cycle, while its transition into apoptosis is attributed to enhanced endoplasmic reticulum(ER)‐stress and phosphatidylethanolamine (PE)‐to‐phosphatidylcholine (PC) metabolic shift. Collectively, this study highlights molecular mechanisms underlying ferroptosis execution, identified a highly predictive ferroptosis gene signature with prognostic value, ferroptosis versus apoptosis biomarkers, and ferroptosis repressors for breast cancer therapy.
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    apoptosis,biomarkers,breast cancer,classification signature,cancer therapy,ferroptosis,TNBC
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    Related Papers

    A Snapshot into the Transcriptomic Landscape of Apoptosis and Ferroptosis in Cancer

    Yaron Vinik,Sima Lev
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    被引用0

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    【要点】：本研究揭示了铁死亡向凋亡转变的分子机制，发现了铁死亡生物标志物和抑制因子，为乳腺癌治疗提供了潜在靶点。
    

    【方法】：通过建立铁死亡至凋亡的连续表型梯度，并结合转录组和代谢组景观进行分析，开发了一种无偏倚的转录组预测器——梯度基因集（GGS）。
    

    【实验】：研究利用了多种铁死亡和凋亡数据集对GGS进行优化，并在体外和体内实验中验证了其准确性。实验结果表明，GGS中的一部分与乳腺癌患者和PDX模型的不良预后相关，并包含不同的铁死亡抑制因子。通过减少PDGFA相关蛋白1（PDAP1）的表达，发现可以抑制基础型乳腺癌在小鼠模型中的生长。研究还发现铁死亡与增强的溶酶体功能、谷氨酰胺分解和三羧酸循环相关，而铁死亡向凋亡的转变与增强的内质网应激和磷脂酸乙醇胺（PE）向磷脂酰胆碱（PC）的代谢转变有关。数据集包括但不限于乳腺癌患者的转录组和代谢组数据。
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