EMBO Molecular MedicinePub Date : 2024-12-01Epub Date: 2024-11-14DOI: 10.1038/s44321-024-00169-0
Ze-Rong Cai, Wen Wang, Di Chen, Hao-Jie Chen, Yan Hu, Xiao-Jing Luo, Yi-Ting Wang, Yi-Qian Pan, Hai-Yu Mo, Shu-Yu Luo, Kun Liao, Zhao-Lei Zeng, Shan-Shan Li, Xin-Yuan Guan, Xin-Juan Fan, Hai-Long Piao, Rui-Hua Xu, Huai-Qiang Ju
{"title":"Diagnosis and prognosis prediction of gastric cancer by high-performance serum lipidome fingerprints.","authors":"Ze-Rong Cai, Wen Wang, Di Chen, Hao-Jie Chen, Yan Hu, Xiao-Jing Luo, Yi-Ting Wang, Yi-Qian Pan, Hai-Yu Mo, Shu-Yu Luo, Kun Liao, Zhao-Lei Zeng, Shan-Shan Li, Xin-Yuan Guan, Xin-Juan Fan, Hai-Long Piao, Rui-Hua Xu, Huai-Qiang Ju","doi":"10.1038/s44321-024-00169-0","DOIUrl":"10.1038/s44321-024-00169-0","url":null,"abstract":"<p><p>Early detection is warranted to improve prognosis of gastric cancer (GC) but remains challenging. Liquid biopsy combined with machine learning will provide new insights into diagnostic strategies of GC. Lipid metabolism reprogramming plays a crucial role in the initiation and development of tumors. Here, we integrated the lipidomics data of three cohorts (n = 944) to develop the lipid metabolic landscape of GC. We further constructed the serum lipid metabolic signature (SLMS) by machine learning, which showed great performance in distinguishing GC patients from healthy donors. Notably, the SLMS also held high efficacy in the diagnosis of early-stage GC. Besides, by performing unsupervised consensus clustering analysis on the lipid metabolic matrix of patients with GC, we generated the gastric cancer prognostic subtypes (GCPSs) with significantly different overall survival. Furthermore, the lipid metabolic disturbance in GC tissues was demonstrated by multi-omics analysis, which showed partially consistent with that in GC serums. Collectively, this study revealed an innovative strategy of liquid biopsy for the diagnosis of GC on the basis of the serum lipid metabolic fingerprints.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3089-3112"},"PeriodicalIF":9.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-28DOI: 10.1038/s44321-024-00155-6
Louise Nuyttens, Jolien Vandewalle, Claude Libert
{"title":"Sepsis-induced changes in pyruvate metabolism: insights and potential therapeutic approaches.","authors":"Louise Nuyttens, Jolien Vandewalle, Claude Libert","doi":"10.1038/s44321-024-00155-6","DOIUrl":"10.1038/s44321-024-00155-6","url":null,"abstract":"<p><p>Sepsis is a heterogeneous syndrome resulting from a dysregulated host response to infection. It is considered as a global major health priority. Sepsis is characterized by significant metabolic perturbations, leading to increased circulating metabolites such as lactate. In mammals, pyruvate is the primary substrate for lactate production. It plays a critical role in metabolism by linking glycolysis, where it is produced, with the mitochondrial oxidative phosphorylation pathway, where it is oxidized. Here, we provide an overview of all cytosolic and mitochondrial enzymes involved in pyruvate metabolism and how their activities are disrupted in sepsis. Based on the available data, we also discuss potential therapeutic strategies targeting these pyruvate-related enzymes leading to enhanced survival.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2678-2698"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-11DOI: 10.1038/s44321-024-00146-7
Yi Guo, Chuanbin Cai, Bingjie Zhang, Bo Tan, Qinmin Tang, Zhifeng Lei, Xiaolan Qi, Jiang Chen, Xiaojiang Zheng, Dan Zi, Song Li, Jun Tan
{"title":"Targeting USP11 regulation by a novel lithium-organic coordination compound improves neuropathologies and cognitive functions in Alzheimer transgenic mice.","authors":"Yi Guo, Chuanbin Cai, Bingjie Zhang, Bo Tan, Qinmin Tang, Zhifeng Lei, Xiaolan Qi, Jiang Chen, Xiaojiang Zheng, Dan Zi, Song Li, Jun Tan","doi":"10.1038/s44321-024-00146-7","DOIUrl":"10.1038/s44321-024-00146-7","url":null,"abstract":"<p><p>Alzheimer's Disease (AD), as the most common neurodegenerative disease worldwide, severely impairs patients' cognitive functions. Although its exact etiology remains unclear, the abnormal aggregations of misfolded β-amyloid peptide and tau protein are considered pivotal in its pathological progression. Recent studies identify ubiquitin-specific protease 11 (USP11) as the key regulator of tau deubiquitination, exacerbating tau aggregation and AD pathology. Thereby, inhibiting USP11 function, via either blocking USP11 activity or lowering USP11 protein level, may serve as an effective therapeutic strategy against AD. Our research introduces IsoLiPro, a unique lithium isobutyrate-L-proline coordination compound, effectively lowers USP11 protein level and enhances tau ubiquitination in vitro. Additionally, long-term oral administration of IsoLiPro dramatically reduces total and phosphorylated tau levels in AD transgenic mice. Moreover, IsoLiPro also significantly lessens β-amyloid deposition and synaptic damage, improving cognitive functions in these animal models. These results indicate that IsoLiPro, as a novel small-molecule USP11 inhibitor, can effectively alleviate AD-like pathologies and improve cognitive functions, offering promise as a potential multi-targeting therapeutic agent against AD.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2856-2881"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-02DOI: 10.1038/s44321-024-00148-5
Jessica P Wiseman, Joseph M Scarrott, João Alves-Cruzeiro, Afshin Saffari, Cedric Böger, Evangelia Karyka, Emily Dawes, Alexandra K Davies, Paolo M Marchi, Emily Graves, Fiona Fernandes, Zih-Liang Yang, Ian Coldicott, Jennifer Hirst, Christopher P Webster, J Robin Highley, Neil Hackett, Adrienn Angyal, Thushan de Silva, Adrian Higginbottom, Pamela J Shaw, Laura Ferraiuolo, Darius Ebrahimi-Fakhari, Mimoun Azzouz
{"title":"Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47.","authors":"Jessica P Wiseman, Joseph M Scarrott, João Alves-Cruzeiro, Afshin Saffari, Cedric Böger, Evangelia Karyka, Emily Dawes, Alexandra K Davies, Paolo M Marchi, Emily Graves, Fiona Fernandes, Zih-Liang Yang, Ian Coldicott, Jennifer Hirst, Christopher P Webster, J Robin Highley, Neil Hackett, Adrienn Angyal, Thushan de Silva, Adrian Higginbottom, Pamela J Shaw, Laura Ferraiuolo, Darius Ebrahimi-Fakhari, Mimoun Azzouz","doi":"10.1038/s44321-024-00148-5","DOIUrl":"10.1038/s44321-024-00148-5","url":null,"abstract":"<p><p>Spastic paraplegia 47 (SPG47) is a neurological disorder caused by mutations in the adaptor protein complex 4 β1 subunit (AP4B1) gene leading to AP-4 complex deficiency. SPG47 is characterised by progressive spastic paraplegia, global developmental delay, intellectual disability and epilepsy. Gene therapy aimed at restoring functional AP4B1 protein levels is a rational therapeutic strategy to ameliorate the disease phenotype. Here we report that a single delivery of adeno-associated virus serotype 9 expressing hAP4B1 (AAV9/hAP4B1) into the cisterna magna leads to widespread gene transfer and restoration of various hallmarks of disease, including AP-4 cargo (ATG9A) mislocalisation, calbindin-positive spheroids in the deep cerebellar nuclei, anatomical brain defects and motor dysfunction, in an SPG47 mouse model. Furthermore, AAV9/hAP4B1-based gene therapy demonstrated a restoration of plasma neurofilament light (NfL) levels of treated mice. Encouraged by these preclinical proof-of-concept data, we conducted IND-enabling studies, including immunogenicity and GLP non-human primate (NHP) toxicology studies. Importantly, NHP safety and biodistribution study revealed no significant adverse events associated with the therapeutic intervention. These findings provide evidence of both therapeutic efficacy and safety, establishing a robust basis for the pursuit of an IND application for clinical trials targeting SPG47 patients.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2882-2917"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-15DOI: 10.1038/s44321-024-00153-8
Nastaran Khazamipour, Htoo Zarni Oo, Nader Al-Nakouzi, Mona Marzban, Nasrin Khazamipour, Morgan E Roberts, Negin Farivar, Igor Moskalev, Joey Lo, Fariba Ghaidi, Irina Nelepcu, Alireza Moeen, Sarah Truong, Robert Dagil, Swati Choudhary, Tobias Gustavsson, Beibei Zhai, Sabine Heitzender, Ali Salanti, Poul H Sorensen, Mads Daugaard
{"title":"Transient CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors.","authors":"Nastaran Khazamipour, Htoo Zarni Oo, Nader Al-Nakouzi, Mona Marzban, Nasrin Khazamipour, Morgan E Roberts, Negin Farivar, Igor Moskalev, Joey Lo, Fariba Ghaidi, Irina Nelepcu, Alireza Moeen, Sarah Truong, Robert Dagil, Swati Choudhary, Tobias Gustavsson, Beibei Zhai, Sabine Heitzender, Ali Salanti, Poul H Sorensen, Mads Daugaard","doi":"10.1038/s44321-024-00153-8","DOIUrl":"10.1038/s44321-024-00153-8","url":null,"abstract":"<p><p>Glycosaminoglycans are often deprioritized as targets for synthetic immunotherapy due to the complexity of glyco-epitopes and limited options for obtaining specific subtype binding. Solid tumors express proteoglycans that are modified with oncofetal chondroitin sulfate (CS), a modification normally restricted to the placenta. Here, we report the design and functionality of transient chimeric antigen receptor (CAR) T cells with selectivity to oncofetal CS. Following expression in T cells, the CAR could be \"armed\" with recombinant VAR2CSA lectins (rVAR2) to target tumor cells expressing oncofetal CS. While unarmed CAR T cells remained inactive in the presence of target cells, VAR2-armed CAR T cells displayed robust activation and the ability to eliminate diverse tumor cell types in vitro. Cytotoxicity of the CAR T cells was proportional to the concentration of rVAR2 available to the CAR, offering a potential molecular handle to finetune CAR T cell activity. In vivo, armed CAR T cells rapidly targeted bladder tumors and increased the survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans may be exploited as potential targets for CAR T cell therapy.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2775-2794"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-28DOI: 10.1038/s44321-024-00149-4
Elisa Cappio Barazzone, Médéric Diard, Isabelle Hug, Louise Larsson, Emma Slack
{"title":"Diagnosing and engineering gut microbiomes.","authors":"Elisa Cappio Barazzone, Médéric Diard, Isabelle Hug, Louise Larsson, Emma Slack","doi":"10.1038/s44321-024-00149-4","DOIUrl":"10.1038/s44321-024-00149-4","url":null,"abstract":"<p><p>The microbes, nutrients and toxins that we are exposed to can have a profound effect on the composition and function of the gut microbiome. Thousands of peer-reviewed publications link microbiome composition and function to health from the moment of birth, right through to centenarians, generating a tantalizing glimpse of what might be possible if we could intervene rationally. Nevertheless, there remain relatively few real-world examples where successful microbiome engineering leads to beneficial health effects. Here we aim to provide a framework for the progress needed to turn gut microbiome engineering from a trial-and-error approach to a rational medical intervention. The workflow starts with truly understanding and accurately diagnosing the problems that we are trying to fix, before moving on to developing technologies that can achieve the desired changes.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2660-2677"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-02DOI: 10.1038/s44321-024-00143-w
Aude Boulay, Emmanuel Quevarec, Isabelle Malet, Giuseppe Nicastro, Célia Chamontin, Suzon Perrin, Corinne Henriquet, Martine Pugnière, Valérie Courgnaud, Mickaël Blaise, Anne-Geneviève Marcelin, Ian A Taylor, Laurent Chaloin, Nathalie J Arhel
{"title":"A new class of capsid-targeting inhibitors that specifically block HIV-1 nuclear import.","authors":"Aude Boulay, Emmanuel Quevarec, Isabelle Malet, Giuseppe Nicastro, Célia Chamontin, Suzon Perrin, Corinne Henriquet, Martine Pugnière, Valérie Courgnaud, Mickaël Blaise, Anne-Geneviève Marcelin, Ian A Taylor, Laurent Chaloin, Nathalie J Arhel","doi":"10.1038/s44321-024-00143-w","DOIUrl":"10.1038/s44321-024-00143-w","url":null,"abstract":"<p><p>HIV-1 capsids cross nuclear pore complexes (NPCs) by engaging with the nuclear import machinery. To identify compounds that inhibit HIV-1 nuclear import, we screened drugs in silico on a three-dimensional model of a CA hexamer bound by Transportin-1 (TRN-1). Among hits, compound H27 inhibited HIV-1 with a low micromolar IC<sub>50</sub>. Unlike other CA-targeting compounds, H27 did not alter CA assembly or disassembly, inhibited nuclear import specifically, and retained antiviral activity against PF74- and Lenacapavir-resistant mutants. The differential sensitivity of divergent primate lentiviral capsids, capsid stability and H27 escape mutants, together with structural analyses, suggest that H27 makes multiple low affinity contacts with assembled capsid. Interaction experiments indicate that H27 may act by preventing CA from engaging with components of the NPC machinery such as TRN-1. H27 exhibited good metabolic stability in vivo and was efficient against different subtypes and circulating recombinant forms from treatment-naïve patients as well as strains resistant to the four main classes of antiretroviral drugs. This work identifies compounds that demonstrate a novel mechanism of action by specifically blocking HIV-1 nuclear import.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2918-2945"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-02DOI: 10.1038/s44321-024-00145-8
Jan Mašek, Iva Filipovic, Noémi Van Hul, Lenka Belicová, Markéta Jiroušková, Daniel V Oliveira, Anna Maria Frontino, Simona Hankeova, Jingyan He, Fabio Turetti, Afshan Iqbal, Igor Červenka, Lenka Sarnová, Elisabeth Verboven, Tomáš Brabec, Niklas K Björkström, Martin Gregor, Jan Dobeš, Emma R Andersson
{"title":"Jag1 insufficiency alters liver fibrosis via T cell and hepatocyte differentiation defects.","authors":"Jan Mašek, Iva Filipovic, Noémi Van Hul, Lenka Belicová, Markéta Jiroušková, Daniel V Oliveira, Anna Maria Frontino, Simona Hankeova, Jingyan He, Fabio Turetti, Afshan Iqbal, Igor Červenka, Lenka Sarnová, Elisabeth Verboven, Tomáš Brabec, Niklas K Björkström, Martin Gregor, Jan Dobeš, Emma R Andersson","doi":"10.1038/s44321-024-00145-8","DOIUrl":"10.1038/s44321-024-00145-8","url":null,"abstract":"<p><p>Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1<sup>Ndr/Ndr</sup> mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1<sup>Ndr/Ndr</sup> mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1<sup>Ndr/Ndr</sup> lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1<sup>-/-</sup> mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1<sup>Ndr/Ndr</sup> lymphocytes were less inflammatory with fewer activated T cells than Jag1<sup>+/+</sup> lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1<sup>-/-</sup> mice with Jag1<sup>Ndr/Ndr</sup> lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1<sup>-/-</sup> mice with Jag1<sup>+/+</sup> lymphocytes. Finally, the Jag1<sup>Ndr/Ndr</sup> hepatocyte expression profile and Treg overrepresentation were corroborated in patients' liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2946-2975"},"PeriodicalIF":11.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-21DOI: 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
{"title":"Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis.","authors":"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","doi":"10.1038/s44321-024-00142-x","DOIUrl":"10.1038/s44321-024-00142-x","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2749-2774"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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