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

Author:

Vinik Yaron1,Maimon Avi1,Dubey Vinay1,Raj Harsha1,Abramovitch Ifat2,Malitsky Sergey3,Itkin Maxim3,Ma'ayan Avi4,Westermann Frank5,Gottlieb Eyal2,Ruppin Eytan6,Lev Sima1ORCID

Affiliation:

1. Molecular Cell Biology Department Weizmann Institute of Science Rehovot 76100 Israel

2. The Ruth and Bruce Rappaport Faculty of Medicine Technion–Israel Institute of Technology Haifa 3525433 Israel

3. Metabolic Profiling Unit Weizmann Institute of Science Rehovot 76100 Israel

4. Department of Pharmacological Sciences Mount Sinai Center for Bioinformatics Icahn School of Medicine at Mount Sinai New York NY 10029 USA

5. Neuroblastoma Genomics German Cancer Research Center (DKFZ) 69120 Heidelberg Germany

6. Cancer Data Science Laboratory National Cancer Institute National Institutes of Health Bethesda MD 20892 USA

Abstract

AbstractFerroptosis 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.

Publisher

Wiley

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