Pub 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
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.
阿尔茨海默病(AD)是全球最常见的神经退行性疾病,严重损害患者的认知功能。虽然其确切病因尚不清楚,但错误折叠的β-淀粉样肽和tau蛋白的异常聚集被认为是其病理发展的关键。最近的研究发现,泛素特异性蛋白酶11(USP11)是tau去泛素化的关键调节因子,会加剧tau的聚集和AD的病理变化。因此,通过阻断USP11活性或降低USP11蛋白水平来抑制USP11功能,可作为一种有效的AD治疗策略。我们的研究引入了一种独特的异丁烯酸锂-L-脯氨酸配位化合物 IsoLiPro,它能有效降低 USP11 蛋白水平并增强体外 tau 泛素化。此外,长期口服 IsoLiPro 能显著降低 AD 转基因小鼠的总 tau 和磷酸化 tau 水平。此外,IsoLiPro 还能显著减少 β 淀粉样蛋白沉积和突触损伤,改善这些动物模型的认知功能。这些结果表明,IsoLiPro 作为一种新型小分子 USP11 抑制剂,能有效缓解 AD 类病理现象并改善认知功能,有望成为一种潜在的多靶点 AD 治疗药物。
{"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}
Pub 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
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.
{"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}
Pub 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
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.
由于糖表位的复杂性和获得特异亚型结合的选择有限,糖胺聚糖通常被排除在合成免疫疗法靶点的优先考虑之外。实体瘤表达的蛋白多糖是由胎盘上的硫酸软骨素(CS)修饰的,这种修饰通常仅限于胎盘。在这里,我们报告了对胎盘上硫酸软骨素具有选择性的瞬时嵌合抗原受体(CAR)T 细胞的设计和功能。在 T 细胞中表达后,CAR 可以用重组 VAR2CSA 凝集素(rVAR2)"武装",以靶向表达胎盘上 CS 的肿瘤细胞。未装备的 CAR T 细胞在靶细胞存在的情况下仍然没有活性,而装备了 VAR2 的 CAR T 细胞则显示出强大的活化能力,并能在体外消除不同类型的肿瘤细胞。CAR T细胞的细胞毒性与CAR可用的rVAR2浓度成正比,这为微调CAR T细胞活性提供了一种潜在的分子处理方法。在体内,武装的 CAR T 细胞能迅速靶向膀胱肿瘤,并提高肿瘤小鼠的存活率。因此,我们的研究表明,癌症限制性糖胺聚糖可被用作 CAR T 细胞疗法的潜在靶点。
{"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}
Pub 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
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 IC50. 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.
HIV-1 包囊通过与核导入机制结合穿过核孔复合体(NPC)。为了找出能抑制 HIV-1 核导入的化合物,我们在运输蛋白-1(TRN-1)结合的 CA 六聚体三维模型上进行了药物筛选。其中,化合物 H27 以较低的微摩尔 IC50 值抑制了 HIV-1。与其他 CA 靶向化合物不同的是,H27 不会改变 CA 的组装或分解,能特异性地抑制核导入,并对 PF74 和来那卡韦耐药突变体保持抗病毒活性。不同灵长类慢病毒噬菌体的不同敏感性、噬菌体稳定性和 H27 逃逸突变体以及结构分析表明,H27 与组装的噬菌体有多种低亲和力接触。相互作用实验表明,H27 可能通过阻止 CA 与 TRN-1 等 NPC 机制成分接触而发挥作用。H27 在体内表现出良好的代谢稳定性,对不同亚型、来自治疗无效患者的循环重组型以及对四大类抗逆转录病毒药物耐药的菌株均有效。这项工作确定了通过特异性阻断 HIV-1 核导入而展示新型作用机制的化合物。
{"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}
Pub 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
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 Jag1Ndr/Ndr 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 Jag1Ndr/Ndr mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1-/- mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1+/+ lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1-/- mice with Jag1Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1-/- mice with Jag1+/+ lymphocytes. Finally, the Jag1Ndr/Ndr 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.
{"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}
Pub 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
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.
{"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}
Hydrocephalus is a common neurological condition, characterized by the excessive accumulation of cerebrospinal fluid in the cerebral ventricles. Primary treatments for hydrocephalus mainly involve neurosurgical cerebrospinal fluid diversion, which hold high morbidity and failure rates, highlighting the necessity for the discovery of novel therapeutic approaches. Although the pathophysiology of hydrocephalus is highly multifactorial, impaired function of the brain ependymal cells plays a fundamental role in hydrocephalus. Here we show that GemC1 and McIdas, key regulators of multiciliated ependymal cell fate determination, induce direct cellular reprogramming towards ependyma. Our study reveals that ectopic expression of GemC1 and McIdas reprograms cortical astrocytes and programs mouse embryonic stem cells into ependyma. McIdas is sufficient to establish functional activity in the reprogrammed astrocytes. Furthermore, we show that McIdas' expression promotes ependymal cell regeneration in two different postnatal hydrocephalus mouse models: an intracranial hemorrhage and a genetic form of hydrocephalus and ameliorates the cytoarchitecture of the neurogenic niche. Our study provides evidence on the restoration of ependyma in animal models mimicking hydrocephalus that could be exploited towards future therapeutic interventions.
{"title":"Ependymal cell lineage reprogramming as a potential therapeutic intervention for hydrocephalus.","authors":"Konstantina Kaplani, Maria-Eleni Lalioti, Styliani Vassalou, Georgia Lokka, Evangelia Parlapani, Georgios Kritikos, Zoi Lygerou, Stavros Taraviras","doi":"10.1038/s44321-024-00156-5","DOIUrl":"10.1038/s44321-024-00156-5","url":null,"abstract":"<p><p>Hydrocephalus is a common neurological condition, characterized by the excessive accumulation of cerebrospinal fluid in the cerebral ventricles. Primary treatments for hydrocephalus mainly involve neurosurgical cerebrospinal fluid diversion, which hold high morbidity and failure rates, highlighting the necessity for the discovery of novel therapeutic approaches. Although the pathophysiology of hydrocephalus is highly multifactorial, impaired function of the brain ependymal cells plays a fundamental role in hydrocephalus. Here we show that GemC1 and McIdas, key regulators of multiciliated ependymal cell fate determination, induce direct cellular reprogramming towards ependyma. Our study reveals that ectopic expression of GemC1 and McIdas reprograms cortical astrocytes and programs mouse embryonic stem cells into ependyma. McIdas is sufficient to establish functional activity in the reprogrammed astrocytes. Furthermore, we show that McIdas' expression promotes ependymal cell regeneration in two different postnatal hydrocephalus mouse models: an intracranial hemorrhage and a genetic form of hydrocephalus and ameliorates the cytoarchitecture of the neurogenic niche. Our study provides evidence on the restoration of ependyma in animal models mimicking hydrocephalus that could be exploited towards future therapeutic interventions.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2725-2748"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521393","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}
Di-(2-ethylhexyl) phthalate (DEHP), an environmental pollutant, has been widely detected in both environmental and clinical samples, representing a serious threat to the homeostasis of the endocrine system. The accumulation of DEHP is notably pronounced in the liver and can lead to liver damage. The lack of effective high-throughput screening system retards the discovery of such drugs that can specifically target and eliminate the detrimental impact of DEHP. Here, by developing a Cy5-modified single-strand DNA-aptamer-based approach targeting DEHP, we have identified luteolin as a potential drug, which showcasing robust efficacy in detoxifying the DEHP by facilitating the expulsion of DEHP in both mouse primary hepatocytes and livers. Mechanistically, luteolin enhances the protein degradation of hepatic urocanate hydratase 1 (Uroc1) by targeting its Ala270 and Val272 sites. More importantly, trans-urocanic acid (trans-UCA), as the substrate of Uroc1, possesses properties similar to luteolin by regulating the lysosomal exocytosis through the inhibition of the ERK1/2 signal cascade. In summary, luteolin serves as a potent therapeutic agent in efficiently detoxifying DEHP in the liver by regulating the UCA/Uroc1 axis.
{"title":"Luteolin detoxifies DEHP and prevents liver injury by degrading Uroc1 protein in mice.","authors":"Huiting Wang, Ziting Zhao, Mingming Song, Wenxiang Zhang, Chang Liu, Siyu Chen","doi":"10.1038/s44321-024-00160-9","DOIUrl":"10.1038/s44321-024-00160-9","url":null,"abstract":"<p><p>Di-(2-ethylhexyl) phthalate (DEHP), an environmental pollutant, has been widely detected in both environmental and clinical samples, representing a serious threat to the homeostasis of the endocrine system. The accumulation of DEHP is notably pronounced in the liver and can lead to liver damage. The lack of effective high-throughput screening system retards the discovery of such drugs that can specifically target and eliminate the detrimental impact of DEHP. Here, by developing a Cy5-modified single-strand DNA-aptamer-based approach targeting DEHP, we have identified luteolin as a potential drug, which showcasing robust efficacy in detoxifying the DEHP by facilitating the expulsion of DEHP in both mouse primary hepatocytes and livers. Mechanistically, luteolin enhances the protein degradation of hepatic urocanate hydratase 1 (Uroc1) by targeting its Ala270 and Val272 sites. More importantly, trans-urocanic acid (trans-UCA), as the substrate of Uroc1, possesses properties similar to luteolin by regulating the lysosomal exocytosis through the inhibition of the ERK1/2 signal cascade. In summary, luteolin serves as a potent therapeutic agent in efficiently detoxifying DEHP in the liver by regulating the UCA/Uroc1 axis.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2699-2724"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544430","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}
Pub Date : 2024-10-30DOI: 10.1038/s44321-024-00161-8
Morgane Fournier, Joaquim Javary, Vincent Roh, Nadine Fournier, Freddy Radtke
Cancer cell plasticity contributes significantly to the failure of chemo- and targeted therapies in triple-negative breast cancer (TNBC). Molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance are largely unknown. Using a genome-wide CRISPR-Cas9 screen, we investigated escape mechanisms of NOTCH-driven TNBC treated with a gamma-secretase inhibitor (GSI) and identified SOX2 as a target of resistance to Notch inhibition. We describe a novel reciprocal inhibitory feedback mechanism between Notch signaling and SOX2. Specifically, Notch signaling inhibits SOX2 expression through its target genes of the HEY family, and SOX2 inhibits Notch signaling through direct interaction with RBPJ. This mechanism shapes divergent cell states with NOTCH positive TNBC being more epithelial-like, while SOX2 expression correlates with epithelial-mesenchymal transition, induces cancer stem cell features and GSI resistance. To counteract monotherapy-induced tumor relapse, we assessed GSI-paclitaxel and dasatinib-paclitaxel combination treatments in NOTCH inhibitor-sensitive and -resistant TNBC xenotransplants, respectively. These distinct preventive combinations and second-line treatment option dependent on NOTCH1 and SOX2 expression in TNBC are able to induce tumor growth control and reduce metastatic burden.
{"title":"Reciprocal inhibition of NOTCH and SOX2 shapes tumor cell plasticity and therapeutic escape in triple-negative breast cancer.","authors":"Morgane Fournier, Joaquim Javary, Vincent Roh, Nadine Fournier, Freddy Radtke","doi":"10.1038/s44321-024-00161-8","DOIUrl":"https://doi.org/10.1038/s44321-024-00161-8","url":null,"abstract":"<p><p>Cancer cell plasticity contributes significantly to the failure of chemo- and targeted therapies in triple-negative breast cancer (TNBC). Molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance are largely unknown. Using a genome-wide CRISPR-Cas9 screen, we investigated escape mechanisms of NOTCH-driven TNBC treated with a gamma-secretase inhibitor (GSI) and identified SOX2 as a target of resistance to Notch inhibition. We describe a novel reciprocal inhibitory feedback mechanism between Notch signaling and SOX2. Specifically, Notch signaling inhibits SOX2 expression through its target genes of the HEY family, and SOX2 inhibits Notch signaling through direct interaction with RBPJ. This mechanism shapes divergent cell states with NOTCH positive TNBC being more epithelial-like, while SOX2 expression correlates with epithelial-mesenchymal transition, induces cancer stem cell features and GSI resistance. To counteract monotherapy-induced tumor relapse, we assessed GSI-paclitaxel and dasatinib-paclitaxel combination treatments in NOTCH inhibitor-sensitive and -resistant TNBC xenotransplants, respectively. These distinct preventive combinations and second-line treatment option dependent on NOTCH1 and SOX2 expression in TNBC are able to induce tumor growth control and reduce metastatic burden.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fragmentomic features of circulating cell free mitochondrial DNA (ccf-mtDNA) including fragmentation profile, 5' end base preference and motif diversity are poorly understood. Here, we generated ccf-mtDNA sequencing data of 1607 plasma samples using capture-based next generation sequencing. We firstly found that fragmentomic features of ccf-mtDNA were remarkably different from those of circulating cell free nuclear DNA. Furthermore, region-specific fragmentomic features of ccf-mtDNA were observed, which was associated with protein binding, base composition and special structure of mitochondrial DNA. When comparing to non-cancer controls, six types of cancer patients exhibited aberrant fragmentomic features. Then, cancer detection models were built based on the fragmentomic features. Both internal and external validation cohorts demonstrated the excellent capacity of our model in distinguishing cancer patients from non-cancer control, with all area under curve higher than 0.9322. The overall accuracy of tissue-of-origin was 89.24% and 87.92% for six cancer types in two validation cohort, respectively. Altogether, our study comprehensively describes cancer-specific fragmentomic features of ccf-mtDNA and provides a proof-of-principle for the ccf-mtDNA fragmentomics-based multi-cancer detection and tissue-of-origin classification.
{"title":"Aberrant fragmentomic features of circulating cell-free mitochondrial DNA as novel biomarkers for multi-cancer detection.","authors":"Yang Liu, Fan Peng, Siyuan Wang, Huanmin Jiao, Miao Dang, Kaixiang Zhou, Wenjie Guo, Shanshan Guo, Huanqin Zhang, Wenjie Song, Jinliang Xing","doi":"10.1038/s44321-024-00163-6","DOIUrl":"https://doi.org/10.1038/s44321-024-00163-6","url":null,"abstract":"<p><p>Fragmentomic features of circulating cell free mitochondrial DNA (ccf-mtDNA) including fragmentation profile, 5' end base preference and motif diversity are poorly understood. Here, we generated ccf-mtDNA sequencing data of 1607 plasma samples using capture-based next generation sequencing. We firstly found that fragmentomic features of ccf-mtDNA were remarkably different from those of circulating cell free nuclear DNA. Furthermore, region-specific fragmentomic features of ccf-mtDNA were observed, which was associated with protein binding, base composition and special structure of mitochondrial DNA. When comparing to non-cancer controls, six types of cancer patients exhibited aberrant fragmentomic features. Then, cancer detection models were built based on the fragmentomic features. Both internal and external validation cohorts demonstrated the excellent capacity of our model in distinguishing cancer patients from non-cancer control, with all area under curve higher than 0.9322. The overall accuracy of tissue-of-origin was 89.24% and 87.92% for six cancer types in two validation cohort, respectively. Altogether, our study comprehensively describes cancer-specific fragmentomic features of ccf-mtDNA and provides a proof-of-principle for the ccf-mtDNA fragmentomics-based multi-cancer detection and tissue-of-origin classification.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}