Cell Metabolism: Get more progress! Shao Zhimin and other teams at Fudan University found that iron death plays an important role in triple-negative breast cancer

On October 17, 2022, Shao Zhimin, Jiang Yizhou and Xiao Yi of Fudan University jointly published a research paper entitled "Ferroptosis heterogeneity in triple-negative breast cancer reveals an innovative immunotherapy combination strategy" online at Cell Metabolism , which integrated multiomics data from the TNBC cohort (n=465) to develop an atlas
of iron death.
This study found that TNBC has a heterogeneous phenotype
in iron death-related metabolites and metabolic pathways.

Triple-negative breast cancer (TNBC) is a biological and clinically heterogeneous disease that accounts for about 15% of diagnosed breast cancer and remains the most difficult subtype
of breast cancer to treat.
Multi-omics studies have provided new insights into the biology and heterogeneity of TNBC and promoted the development of
precision therapy.
Previous work has described the transcriptomics, genomics, and metabolomics landscape of TNBCs in Chinese populations to illustrate their heterogeneity
in molecular signature, metabolic reprogramming, and tumor microenvironment.

Based on these findings, the researchers proposed a TNBC classification system with four subtypes: mesenchymal-like (MES), luminal androgen receptor (LAR), immunomodulatory (IM), and basal and immunosuppressive (BLIS) subtypes
.
In addition, the researchers proposed several potential therapeutic targets for each subtype and conducted a FUTURE trial (ClinicalTrials.
gov, NCT03805399) to verify the effectiveness of
these targeted therapies.
Although objective response rates have improved overall compared to conventional chemotherapy, some clades, such as AR inhibitors plus CDK4/6 inhibitors, are less effective than expected
in LAR subtype B.

Article pattern diagram (image from Cell Metabolism)

Iron death is a non-apoptotic and iron-dependent form of cell death that peaks
in excessive lipid peroxidation downstream of metabolic dysfunction.
Cell death due to iron death is done by phospholipid peroxidation (OxPE, phosphatidylethanolamine oxide), a process catalyzed by lipoxygenases that rely on metallic iron, reactive oxygen species (ROS), and phospholipids
containing polyunsaturated fatty acid chains (PE-PUFAs).
On the other hand, cells have evolved at least three defense mechanisms against iron death: the glutathione (GSH) system, the coenzyme Q10 (CoQ10) system, and the thioredoxin (TXN) system detoxify lipid hydrogen peroxide and inhibit iron death
.

Induction of iron death is an explorable treatment strategy because TNBC is a tumor
rich in iron and lipids.
Importantly, interventions in lipid metabolism or redox balance can lead to iron death
in multiple cancers.
However, recent research on iron death in the context of breast cancer has focused on the exploration of new molecules that regulate iron death and the development
of novel nanoparticles.
Considering that iron death is a gradual process regulated by multiple metabolic pathways, a clear picture of iron death in TNBC remains unrevealed
.

In this study, comprehensive multiomics data from a large TNBC cohort were used to explore iron mortality in TNBC
.
Four TNBC subtypes exhibit heterogeneous ferrogenesis phenotypes
at the transcriptome and metabolome levels.
Cross-referencing with genomic alterations further reveals key drivers of
iron death.
Strikingly, the researchers proposed and experimentally validated a combination therapy
of GSH peroxidase 4 (GPX4) inhibitor and immune checkpoint blockade for LAR tumors.

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