Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis.

IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EMBO Molecular Medicine Pub Date : 2024-11-01 Epub Date: 2024-10-21 DOI:10.1038/s44321-024-00142-x
Tobias Ackermann, Engy Shokry, Ruhi Deshmukh, Jayanthi Anand, Laura C A Galbraith, Louise Mitchell, Giovanny Rodriguez-Blanco, Victor H Villar, Britt Amber Sterken, Colin Nixon, Sara Zanivan, Karen Blyth, David Sumpton, Saverio Tardito
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Abstract

The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation and counteracted by the antioxidant activity of the selenoprotein GPX4. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies at low density. We found that secretion of the anti-ferroptotic factors, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the low expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of Sec-tRNAsec biosynthesis, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour.

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乳腺癌会分泌抗发酵的 MUFAs,并依赖硒蛋白合成实现转移。
三阴性乳腺癌(TNBC)患者的治疗方案有限,导致转移性复发率高、预后差。铁中毒是一种由铁依赖的脂质过氧化引起的细胞死亡,硒蛋白 GPX4 的抗氧化活性可抵消铁中毒。在这里,我们发现 TNBC 细胞在高密度培养时会在细胞外环境中分泌一种抗铁细胞凋亡因子,但在低密度形成集落时则会发生铁细胞凋亡。我们发现,含有单不饱和脂肪酸(MUFA)的脂质是抗铁中毒因子的分泌物,单细胞是否容易发生铁中毒取决于硬脂酰-CoA 去饱和酶(SCD)的低表达量,而这种表达量与细胞密度成正比。最后,我们表明,Sec-tRNAsec 生物合成是产生硒蛋白的一个重要步骤,它的抑制会导致铁变态反应,并损害循环 TNBC 细胞的肺部播种,这些细胞不再受到原发肿瘤富含 MUFA 环境的保护。
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来源期刊
EMBO Molecular Medicine
EMBO Molecular Medicine 医学-医学:研究与实验
CiteScore
17.70
自引率
0.90%
发文量
105
审稿时长
4-8 weeks
期刊介绍: EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)
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