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Rett syndrome: interferon-γ to the rescue? 雷特综合征:干扰素-γ能救命吗?
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-04 DOI: 10.1038/s44321-024-00154-7
Richard R Meehan, Sari Pennings
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引用次数: 0
Reciprocal inhibition of NOTCH and SOX2 shapes tumor cell plasticity and therapeutic escape in triple-negative breast cancer. NOTCH和SOX2的相互抑制塑造了肿瘤细胞的可塑性和三阴性乳腺癌的治疗逃逸。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-30 DOI: 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.

癌细胞可塑性是三阴性乳腺癌(TNBC)化疗和靶向治疗失败的重要原因。治疗诱导的肿瘤细胞可塑性及相关耐药性的分子机制在很大程度上尚属未知。通过全基因组 CRISPR-Cas9 筛选,我们研究了用γ-分泌酶抑制剂(GSI)治疗 NOTCH 驱动的 TNBC 的逃逸机制,并确定 SOX2 为 Notch 抑制的耐药靶点。我们描述了Notch信号传导与SOX2之间一种新型的相互抑制反馈机制。具体来说,Notch信号通过其HEY家族的靶基因抑制SOX2的表达,而SOX2则通过与RBPJ的直接相互作用抑制Notch信号。这种机制形成了不同的细胞状态,Notch 阳性的 TNBC 更像上皮细胞,而 SOX2 的表达则与上皮-间质转化相关,诱导癌症干细胞特征和 GSI 抗性。为了应对单药治疗诱导的肿瘤复发,我们分别在对NOTCH抑制剂敏感和耐药的TNBC异种移植中评估了GSI-紫杉醇和达沙替尼-紫杉醇联合疗法。这些不同的预防性组合和二线治疗方案依赖于 TNBC 中 NOTCH1 和 SOX2 的表达,能够诱导肿瘤生长控制并减少转移负荷。
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引用次数: 0
Aberrant fragmentomic features of circulating cell-free mitochondrial DNA as novel biomarkers for multi-cancer detection. 将循环细胞游离线粒体 DNA 的异常片段组特征作为检测多种癌症的新型生物标记物。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-30 DOI: 10.1038/s44321-024-00163-6
Yang Liu, Fan Peng, Siyuan Wang, Huanmin Jiao, Miao Dang, Kaixiang Zhou, Wenjie Guo, Shanshan Guo, Huanqin Zhang, Wenjie Song, Jinliang Xing

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.

人们对循环游离细胞线粒体 DNA(ccf-mtDNA)的片段组学特征,包括片段轮廓、5'端碱基偏好和基序多样性知之甚少。在此,我们利用基于捕获的新一代测序技术,对1607份血浆样本进行了ccf-mtDNA测序。我们首先发现,ccf-mtDNA的片段组特征与循环细胞游离核DNA的片段组特征明显不同。此外,我们还观察到ccf-mtDNA的区域特异性片段组特征,这与线粒体DNA的蛋白质结合、碱基组成和特殊结构有关。与非癌症对照组相比,六种癌症患者表现出异常片段组特征。然后,根据片段组特征建立了癌症检测模型。内部和外部验证组群都证明了我们的模型在区分癌症患者和非癌症对照组方面的卓越能力,所有模型的曲线下面积都高于 0.9322。在两个验证队列中,六种癌症类型的原发组织总体准确率分别为 89.24% 和 87.92%。总之,我们的研究全面描述了ccf-mtDNA的癌症特异性片段组学特征,为基于ccf-mtDNA片段组学的多癌症检测和原发组织分类提供了原理性证明。
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引用次数: 0
Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas. 针对 ADAM12 的纤维化疫苗接种可减少临床前胰腺腺癌中的脱落细胞。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-30 DOI: 10.1038/s44321-024-00157-4
Jing Chen, Michal Sobecki, Ewelina Krzywinska, Kevin Thierry, Mélissa Masmoudi, Shunmugam Nagarajan, Zheng Fan, Jingyi He, Irina Ferapontova, Eric Nelius, Frauke Seehusen, Dagmar Gotthardt, Norihiko Takeda, Lukas Sommer, Veronika Sexl, Christian Münz, David DeNardo, Ana Hennino, Christian Stockmann

A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.g., the disintegrin metalloprotease, ADAM12. Previous studies have shown that immunotherapeutic ablation of ADAM12+ cells reduces fibrosis in various organs. In preclinical mouse models of PDAC, we observe ADAM12 expression in CAFs as well as in tumor cells but not in healthy mouse pancreas. Therefore, we tested prophylactic and therapeutic vaccination against ADAM12 in murine PDAC and observed delayed tumor growth along with a reduction in CAFs and tumor desmoplasia. This is furthermore associated with vascular normalization and alleviated tumor hypoxia. The ADAM12 vaccine induces a redistribution of CD8+ T cells within the tumor and cytotoxic responses against ADAM12+ cells. In summary, vaccination against the endogenous fibroblast target ADAM12 effectively depletes CAFs, reduces desmoplasia and delays the growth of murine PDACs. These results provide proof-of-principle for the development of vaccination-based immunotherapies to treat tumor desmoplasia.

胰腺导管腺癌(PDAC)的一个标志性特征是大量瘤内纤维化,即脱落细胞增多症(desmoplasia)。脱模增生的特点是癌相关成纤维细胞(CAFs)的扩张和细胞外基质(ECM)的大量增加。在纤维形成过程中,不同的基因会在成纤维细胞中重新激活,例如崩解金属蛋白酶 ADAM12。先前的研究表明,通过免疫治疗消减 ADAM12+ 细胞可减少各种器官的纤维化。在 PDAC 临床前小鼠模型中,我们观察到 ADAM12 在 CAFs 和肿瘤细胞中的表达,但在健康小鼠胰腺中却没有发现。因此,我们在小鼠 PDAC 中测试了针对 ADAM12 的预防性和治疗性疫苗接种,观察到肿瘤生长延迟、CAFs 减少和肿瘤脱钙化。这还与血管正常化和肿瘤缺氧缓解有关。ADAM12 疫苗能诱导肿瘤内 CD8+ T 细胞重新分布,并诱导针对 ADAM12+ 细胞的细胞毒性反应。总之,针对内源性成纤维细胞靶标 ADAM12 的疫苗接种能有效地消耗 CAFs、减少脱钙并延缓小鼠 PDAC 的生长。这些结果为开发基于疫苗的免疫疗法治疗肿瘤脱钙提供了原理性证明。
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引用次数: 0
Liver DE(HP)toxification: luteolin as "phthalates-cleaner" to protect from environmental pollution. 肝脏 DE(HP)中毒:叶黄素作为 "邻苯二甲酸盐清洁剂",可防止环境污染。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-29 DOI: 10.1038/s44321-024-00158-3
Federica Cappelli, Alessandro Mengozzi
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引用次数: 0
Luteolin detoxifies DEHP and prevents liver injury by degrading Uroc1 protein in mice. 叶黄素通过降解小鼠体内的 Uroc1 蛋白,为 DEHP 解毒并防止肝损伤。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-29 DOI: 10.1038/s44321-024-00160-9
Huiting Wang, Ziting Zhao, Mingming Song, Wenxiang Zhang, Chang Liu, Siyu Chen

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.

邻苯二甲酸二(2-乙基己基)酯(DEHP)是一种环境污染物,在环境和临床样本中被广泛检测到,对内分泌系统的平衡构成严重威胁。DEHP 在肝脏中的蓄积尤为明显,可导致肝损伤。由于缺乏有效的高通量筛选系统,阻碍了能特异性靶向消除 DEHP 有害影响的药物的发现。在这里,通过开发一种基于Cy5修饰的单链DNA-aptamer方法来靶向DEHP,我们发现了木犀草素这种潜在的药物,它通过促进小鼠原代肝细胞和肝脏中DEHP的排出,在DEHP的解毒方面显示出强大的功效。从机理上讲,木犀草素通过靶向肝脏尿氨酸水解酶1(Uroc1)的Ala270和Val272位点,促进其蛋白质降解。更重要的是,反式尿囊酸(trans-UCA)作为 Uroc1 的底物,通过抑制 ERK1/2 信号级联调节溶酶体的外泌,具有与叶黄素类似的特性。总之,通过调节 UCA/Uroc1 轴,木犀草素可作为一种有效的治疗药物,在肝脏中有效地解毒 DEHP。
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引用次数: 0
Sepsis-induced changes in pyruvate metabolism: insights and potential therapeutic approaches. 败血症诱发的丙酮酸代谢变化:见解和潜在的治疗方法。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-28 DOI: 10.1038/s44321-024-00155-6
Louise Nuyttens, Jolien Vandewalle, Claude Libert

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.

败血症是由于宿主对感染的反应失调而导致的一种异质性综合征。它被视为全球主要的健康优先事项。败血症的特点是新陈代谢严重紊乱,导致乳酸等循环代谢物增加。在哺乳动物体内,丙酮酸是产生乳酸的主要底物。丙酮酸在新陈代谢中起着关键作用,它将产生丙酮酸的糖酵解与氧化丙酮酸的线粒体氧化磷酸化途径连接起来。在此,我们概述了参与丙酮酸代谢的所有细胞膜和线粒体酶,以及它们在败血症中的活动是如何被破坏的。根据现有数据,我们还讨论了针对这些丙酮酸相关酶的潜在治疗策略,以提高存活率。
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引用次数: 0
Diagnosing and engineering gut microbiomes. 诊断和改造肠道微生物组。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-28 DOI: 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.

我们接触的微生物、营养物质和毒素会对肠道微生物组的组成和功能产生深远影响。成千上万篇经同行评审的论文将微生物组的组成和功能与健康联系在一起,从婴儿出生到百岁老人,让人看到了如果我们能够合理干预可能实现的前景。然而,在现实世界中,成功的微生物组工程对健康产生有益影响的例子仍然相对较少。在此,我们旨在为将肠道微生物组工程从试错方法转变为理性医疗干预所需的进展提供一个框架。工作流程首先要真正理解并准确诊断我们试图解决的问题,然后再开发能够实现预期变化的技术。
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引用次数: 0
Ependymal cell lineage reprogramming as a potential therapeutic intervention for hydrocephalus. 脑外膜细胞系重编程作为治疗脑积水的一种潜在干预措施。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-28 DOI: 10.1038/s44321-024-00156-5
Konstantina Kaplani, Maria-Eleni Lalioti, Styliani Vassalou, Georgia Lokka, Evangelia Parlapani, Georgios Kritikos, Zoi Lygerou, Stavros Taraviras

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.

脑积水是一种常见的神经系统疾病,其特点是脑脊液在脑室过度积聚。脑积水的主要治疗方法是通过神经外科手术进行脑脊液引流,但这种方法的发病率和失败率都很高,因此有必要探索新的治疗方法。虽然脑积水的病理生理学具有高度的多因素性,但脑外膜细胞功能受损在脑积水中起着根本性的作用。在这里,我们发现 GemC1 和 McIdas(多纤毛外膜细胞命运决定的关键调控因子)可诱导细胞直接向外膜重编程。我们的研究发现,异位表达GemC1和McIdas可以重编程大脑皮层星形胶质细胞,并将小鼠胚胎干细胞编程为外膜。McIdas足以在重编程的星形胶质细胞中建立功能活性。此外,我们还发现,McIdas的表达可促进两种不同的出生后脑积水小鼠模型(颅内出血和遗传性脑积水)中的外膜细胞再生,并改善神经源龛的细胞结构。我们的研究提供了在模拟脑积水的动物模型中恢复外膜的证据,可用于未来的治疗干预。
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引用次数: 0
Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis. 乳腺癌会分泌抗发酵的 MUFAs,并依赖硒蛋白合成实现转移。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub 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

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.

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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引用次数: 0
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EMBO Molecular Medicine
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