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An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress. 新陈代谢调整的内在机制促进了心脏对压力的恢复能力。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-13 DOI: 10.1038/s44321-024-00132-z
Matteo Sorge,Giulia Savoré,Andrea Gallo,Davide Acquarone,Mauro Sbroggiò,Silvia Velasco,Federica Zamporlini,Saveria Femminò,Enrico Moiso,Giampaolo Morciano,Elisa Balmas,Andrea Raimondi,Gabrielle Nattenberg,Rachele Stefania,Carlo Tacchetti,Angela Maria Rizzo,Paola Corsetto,Alessandra Ghigo,Emilia Turco,Fiorella Altruda,Lorenzo Silengo,Paolo Pinton,Nadia Raffaelli,Nathan J Sniadecki,Claudia Penna,Pasquale Pagliaro,Emilio Hirsch,Chiara Riganti,Guido Tarone,Alessandro Bertero,Mara Brancaccio
Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overload and doxorubicin treatment, preventing mitochondrial dysfunction. Accordingly, the treatment with the lipid oxidation inhibitor Trimetazidine concomitantly with stressful stimuli limits ROS accumulation and prevents long-term heart dysfunction. These findings disclose a physiologic mechanism of metabolic regulation in the heart and demonstrate that a timely restriction of lipid metabolism represents a potential therapeutic strategy to improve cardiac resilience to stress.
要找到保护心脏的有效方法,确定心脏复原力的分子机制至关重要。心脏通过脂肪酸氧化产生生理水平的 ROS,但应激事件会增加 ROS,导致线粒体功能障碍和心脏功能损伤。Melusin 是一种肌肉特异性伴侣蛋白,在应激过程中对心肌代偿性重塑是必需的。我们在此报告了 Melusin 在线粒体中的定位,它与线粒体三功能蛋白(脂肪酸氧化的关键酶)结合并降低其活性。通过研究小鼠和人类诱导多能干细胞衍生的心肌细胞,我们发现 Melusin 可减少心肌中的脂质氧化,并在稳态、压力过载和多柔比星治疗期间限制 ROS 的产生,从而防止线粒体功能障碍。因此,在压力刺激下同时使用脂质氧化抑制剂曲美他嗪治疗可限制 ROS 的积累,防止长期心脏功能障碍。这些发现揭示了心脏代谢调节的生理机制,并证明及时限制脂质代谢是提高心脏抗应激能力的一种潜在治疗策略。
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引用次数: 0
CRISPR-enabled point-of-care genotyping for APOL1 genetic risk assessment. 用于 APOL1 遗传风险评估的 CRISPR 支持的护理点基因分型。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-13 DOI: 10.1038/s44321-024-00126-x
Robert Greensmith,Isadora T Lape,Cristian V Riella,Alexander J Schubert,Jakob J Metzger,Anand S Dighe,Xiao Tan,Bernhard Hemmer,Josefine Rau,Sarah Wendlinger,Nora Diederich,Anja Schütz,Leonardo V Riella,Michael M Kaminski
Detecting genetic variants enables risk factor identification, disease screening, and initiation of preventative therapeutics. However, current methods, relying on hybridization or sequencing, are unsuitable for point-of-care settings. In contrast, CRISPR-based-diagnostics offer high sensitivity and specificity for point-of-care applications. While these methods have predominantly been used for pathogen sensing, their utilization for genotyping is limited. Here, we report a multiplexed CRISPR-based genotyping assay using LwaCas13a, PsmCas13b, and LbaCas12a, enabling the simultaneous detection of six genotypes. We applied this assay to identify genetic variants in the APOL1 gene prevalent among African Americans, which are associated with an 8-30-fold increase in the risk of developing kidney disease. Machine learning facilitated robust analysis across a multicenter clinical cohort of more than 100 patients, accurately identifying their genotypes. In addition, we optimized the readout using a multi-analyte lateral-flow assay demonstrating the ability for simplified genotype determination of clinical samples. Our CRISPR-based genotyping assay enables cost-effective point-of-care genetic variant detection due to its simplicity, versatility, and fast readout.
检测基因变异有助于识别风险因素、筛查疾病和启动预防性疗法。然而,目前依赖杂交或测序的方法并不适合在护理点环境中使用。相比之下,基于 CRISPR 的诊断方法具有高灵敏度和高特异性,可用于护理点应用。虽然这些方法主要用于病原体检测,但在基因分型方面的应用却很有限。在此,我们报告了一种基于 CRISPR 的多重基因分型检测方法,该方法使用 LwaCas13a、PsmCas13b 和 LbaCas12a,可同时检测六种基因型。我们应用这种检测方法鉴定了非裔美国人中普遍存在的 APOL1 基因中的遗传变异,这些变异与肾病患病风险增加 8-30 倍有关。机器学习有助于对 100 多名患者的多中心临床队列进行稳健分析,准确确定他们的基因型。此外,我们还利用多分析横向流动测定法优化了读出结果,证明了简化临床样本基因型测定的能力。我们基于CRISPR的基因分型测定因其简便性、多功能性和快速读出,实现了具有成本效益的床旁基因变异检测。
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引用次数: 0
A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death. HNF4α在多微生物败血症相关代谢重编程和死亡中的关键作用
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-11 DOI: 10.1038/s44321-024-00130-1
Céline Van Dender,Steven Timmermans,Ville Paakinaho,Tineke Vanderhaeghen,Jolien Vandewalle,Maarten Claes,Bruno Garcia,Bart Roman,Jan De Waele,Siska Croubels,Karolien De Bosscher,Philip Meuleman,Antoine Herpain,Jorma J Palvimo,Claude Libert
In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis, and organ damage and prevents an adequate response to IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in tolerance to sepsis. In conclusion, hepatic HNF4α activity is decreased during sepsis, causing PPARα downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis.
在败血症中,有限的食物摄入量和增加的能量消耗会诱发饥饿反应,而肝脏 PPARα 表达的快速下降会损害这种反应,PPARα 是细胞内游离脂肪酸分解过程中必不可少的转录因子。PPARα 下调的上游机制尚不清楚。我们发现脓毒症会导致肝脏 HNF4α 逐渐丧失功能,而 HNF4α 对包括 PPARα 在内的几种重要核受体的表达有很大影响。肝细胞中 HNF4α 的耗竭会显著增加败血症致死率、脂肪变性和器官损伤,并阻止对 IL6 的充分反应,而 IL6 对肝脏再生和存活至关重要。HNF4α激动剂能在所有水平上防止败血症,而与细菌负荷无关,这表明HNF4α对败血症的耐受性至关重要。总之,脓毒症期间肝脏 HNF4α 活性降低,导致 PPARα 下调、代谢问题和 IL6 介导的急性期反应紊乱。这些发现为脓毒症提供了新的见解和治疗方案。
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引用次数: 0
Trained immunity of intestinal tuft cells during infancy enhances host defense against enteroviral infections in mice. 婴儿期肠簇细胞的免疫训练可增强小鼠宿主对肠道病毒感染的防御能力。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-11 DOI: 10.1038/s44321-024-00128-9
Deyan Chen,Jing Wu,Fang Zhang,Ruining Lyu,Qiao You,Yajie Qian,Yurong Cai,Xiaoyan Tian,Hongji Tao,Yating He,Waqas Nawaz,Zhiwei Wu
Innate immune cells have been acknowledged as trainable in recent years. While intestinal tuft cells are recognized for their crucial roles in the host defense against intestinal pathogens, there remains uncertainty regarding their trainability. Enterovirus 71 (EV71), a prevalent enterovirus that primarily infects children but rarely infects adults. At present, there is a significant expansion of intestinal tuft cells in the EV71-infected mouse model, which is associated with EV71-induced interleukin-25 (IL-25) production. Further, we found that IL-25 pre-treatment at 2 weeks old mouse enabled tuft cells to acquire immune memory. This was evidenced by the rapid expansion and stronger response of IL-25-trained tuft cells in response to EV71 infection at 6 weeks old, surpassing the reactivity of naïve tuft cells in mice without IL-25-trained progress. Interestingly, IL-25-trained intestinal tuft cells exhibit anti-enteroviral effect via producing a higher level of IL-25. Mechanically, IL-25 treatment upregulates spermidine/spermine acetyl-transferase enzyme (SAT1) expression, mediates intracellular polyamine deficiency, further inhibits enterovirus replication. In summary, tuft cells can be trained by IL-25, which supports faster and higher level IL-25 production in response to EV71 infection and further exhibits anti-enteroviral effect via SAT1-mediated intracellular polyamine deficiency. Given that IL-25 can be induced by multiple gut microbes during human growth and development, including shifts in gut flora abundance, which may partially explain the different susceptibility to enteroviral infections between adults and children.
近年来,先天性免疫细胞被认为是可以训练的。虽然肠套叠细胞在宿主防御肠道病原体的过程中发挥着至关重要的作用,但其可训练性仍存在不确定性。肠道病毒 71(EV71)是一种流行的肠道病毒,主要感染儿童,但很少感染成人。目前,在 EV71 感染的小鼠模型中,肠绒毛细胞显著扩张,这与 EV71 诱导的白细胞介素-25(IL-25)分泌有关。此外,我们还发现,在小鼠2周大时进行IL-25预处理可使肠套叠细胞获得免疫记忆。经过IL-25训练的簇细胞在6周大时对EV71感染的反应迅速扩大且反应更强,超过了没有经过IL-25训练的小鼠幼稚簇细胞的反应性,这就是证明。有趣的是,经过IL-25训练的肠绒毛细胞通过产生更高水平的IL-25表现出抗肠病毒作用。从机理上讲,IL-25处理可上调精胺/精胺乙酰转移酶(SAT1)的表达,介导细胞内多胺的缺乏,进一步抑制肠道病毒的复制。总之,IL-25可训练丛细胞,使其在应对EV71感染时产生更快、更高水平的IL-25,并通过SAT1介导的细胞内多胺缺乏进一步发挥抗肠病毒作用。鉴于IL-25可在人体生长发育过程中由多种肠道微生物诱导,包括肠道菌群丰度的变化,这可能部分解释了成人和儿童对肠道病毒感染的易感性不同。
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引用次数: 0
The RhoB p.S73F mutation leads to cerebral palsy through dysregulation of lipid homeostasis. RhoB p.S73F突变通过脂质平衡失调导致脑瘫。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-07-30 DOI: 10.1038/s44321-024-00113-2
Xinyu Wu, Ruonan Liu, Zhongtian Zhang, Jie Yang, Xin Liu, Liqiang Jiang, Mengmeng Fang, Shoutang Wang, Liangxue Lai, Yuning Song, Zhanjun Li

Cerebral palsy (CP) is a prevalent neurological disorder that imposes a significant burden on children, families, and society worldwide. Recently, the RhoB p.S73F mutation was identified as a de novo mutation associated with CP. However, the mechanism by which the RhoB p.S73F mutation causes CP is currently unclear. In this study, rabbit models were generated to mimic the human RhoB p.S73F mutation using the SpG-BE4max system, and exhibited the typical symptoms of human CP, such as periventricular leukomalacia and spastic-dystonic diplegia. Further investigation revealed that the RhoB p.S73F mutation could activate ACAT1 through the LYN pathway, and the subsequently altered lipid levels may lead to neuronal and white matter damage resulting in the development of CP. This study presented the first mammalian model of genetic CP that accurately replicates the RhoB p.S73F mutation in humans, provided further insights between RhoB and lipid metabolism, and novel therapeutic targets for human CP.

脑性瘫痪(CP)是一种常见的神经系统疾病,给全世界的儿童、家庭和社会带来了沉重的负担。最近,RhoB p.S73F突变被确定为与CP相关的新突变。然而,RhoB p.S73F突变导致CP的机制目前尚不清楚。本研究利用 SpG-BE4max 系统生成了模拟人类 RhoB p.S73F 突变的家兔模型,该模型表现出人类 CP 的典型症状,如脑室周围白斑和痉挛性肌张力障碍性截瘫。进一步研究发现,RhoB p.S73F突变可通过LYN途径激活ACAT1,随后脂质水平的改变可能导致神经元和白质损伤,从而导致CP的发生。这项研究首次提出了准确复制人类 RhoB p.S73F 突变的遗传性 CP 哺乳动物模型,进一步揭示了 RhoB 与脂质代谢之间的关系,并提出了人类 CP 的新治疗靶点。
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引用次数: 0
"Cruising together"-ASC specks and SAA, a perfect match in chronic inflammation. "同舟共济"--ASC斑点和SAA,慢性炎症的绝配。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-07-30 DOI: 10.1038/s44321-024-00109-y
Salie Maasewerd, Bernardo Simoes Franklin
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引用次数: 0
Histidine-rich glycoprotein modulates neutrophils and thrombolysis-associated hemorrhagic transformation. 富含组氨酸糖蛋白可调节中性粒细胞和溶栓相关出血转化。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-15 DOI: 10.1038/s44321-024-00117-y
Wei Jiang, Yuexin Zhao, Rongrong Liu, Bohao Zhang, Yuhan Xie, Bin Gao, Kaibin Shi, Ming Zou, Dongmei Jia, Jiayue Ding, Xiaowei Hu, Yanli Duan, Ranran Han, DeRen Huang, Luc Van Kaer, Fu-Dong Shi

Intravenous thrombolysis using recombinant tissue plasminogen activator (tPA) remains the primary treatment for patients with acute ischemic stroke (AIS). However, the mechanism of tPA-related hemorrhagic transformation (HT) remains poorly understood. Elevation of histidine-rich glycoprotein (HRG) expression was detected by nano-liquid chromatography tandem mass spectrometry at 1 h following tPA infusion as compared to baseline prior to tPA infusion (discovery cohort, n = 10), which was subsequently confirmed in a validation cohort (n = 157) by ELISA. Surprisingly, no elevation of HRG was detected in individuals who subsequently developed HT. During in vitro experiments, HRG reduced neutrophil NETosis, inflammatory cytokine production, and migration across the blood-brain barrier induced by tPA. In a photothrombotic murine AIS model, HRG administration ameliorated HT with delayed thrombolysis, by inhibiting neutrophil immune infiltration and downregulating pro-inflammatory signaling pathways. Neutrophil depletion or NETosis inhibition also alleviated HT, whereas HRG siRNA treatment exacerbated HT. In conclusion, fluctuations in HRG levels may reflect tPA therapy and its associated HT. The inhibitory effect of HRG on neutrophils may counteract tPA-induced immune abnormalities and HT in patients with AIS.

使用重组组织浆细胞酶原激活剂(tPA)进行静脉溶栓仍是急性缺血性卒中(AIS)患者的主要治疗方法。然而,人们对与 tPA 相关的出血性转化(HT)的机制仍知之甚少。通过纳米液相色谱串联质谱法检测到输注 tPA 后 1 小时富含组氨酸糖蛋白(HRG)的表达高于输注 tPA 前的基线(发现队列,n = 10),随后通过 ELISA 法在验证队列(n = 157)中证实了这一点。令人惊讶的是,在随后发生 HT 的个体中未检测到 HRG 升高。在体外实验中,HRG可减少中性粒细胞的NETosis、炎症细胞因子的产生以及tPA诱导的血脑屏障迁移。在光血栓小鼠 AIS 模型中,HRG 通过抑制中性粒细胞免疫浸润和下调促炎信号通路,改善了延迟溶栓的 HT。中性粒细胞耗竭或NETosis抑制也能缓解HT,而HRG siRNA处理则会加重HT。总之,HRG 水平的波动可能反映了 tPA 治疗及其相关的 HT。HRG 对中性粒细胞的抑制作用可能会抵消 tPA 诱导的 AIS 患者免疫异常和 HT。
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引用次数: 0
Therapeutic targeting ERRγ suppresses metastasis via extracellular matrix remodeling in small cell lung cancer. 针对ERRγ的治疗可通过细胞外基质重塑抑制小细胞肺癌的转移。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-07-31 DOI: 10.1038/s44321-024-00108-z
Hong Wang, Huizi Sun, Jie Huang, Zhenhua Zhang, Guodi Cai, Chaofan Wang, Kai Xiao, Xiaofeng Xiong, Jian Zhang, Peiqing Liu, Xiaoyun Lu, Weineng Feng, Junjian Wang

Small-cell lung cancer (SCLC) is the most aggressive and lethal type of lung cancer, characterized by limited treatment options, early and frequent metastasis. However, the determinants of metastasis in SCLC are poorly defined. Here, we show that estrogen-related receptor gamma (ERRγ) is overexpressed in metastatic SCLC tumors, and is positively associated with SCLC progression. ERRγ functions as an essential activator of extracellular matrix (ECM) remodeling and cell adhesion, two critical steps in metastasis, by directly regulating the expression of major genes involved in these processes. Genetic and pharmacological inhibition of ERRγ markedly reduces collagen production, cell-matrix adhesion, microfilament production, and eventually blocks SCLC cell invasion and tumor metastasis. Notably, ERRγ antagonists significantly suppressed tumor growth and metastasis and restored SCLC vulnerability to chemotherapy in multiple cell-derived and patient-derived xenograft models. Taken together, these findings establish ERRγ as an attractive target for metastatic SCLC and provide a potential pharmacological strategy for treating this lethal disease.

小细胞肺癌(SCLC)是最具侵袭性和致命性的肺癌类型,其特点是治疗方案有限、转移早且频繁。然而,小细胞肺癌转移的决定因素尚未明确。在这里,我们发现雌激素相关受体γ(ERRγ)在转移性SCLC肿瘤中过度表达,并且与SCLC的进展呈正相关。ERRγ是细胞外基质(ECM)重塑和细胞粘附(转移的两个关键步骤)的重要激活剂,它直接调控参与这些过程的主要基因的表达。遗传和药物抑制ERRγ可显著减少胶原蛋白的产生、细胞-基质粘附和微丝的产生,并最终阻止SCLC细胞的侵袭和肿瘤转移。值得注意的是,ERRγ拮抗剂能显著抑制肿瘤的生长和转移,并在多种细胞来源和患者来源的异种移植模型中恢复SCLC对化疗的易感性。综上所述,这些发现确立了ERRγ作为转移性SCLC的一个有吸引力的靶点,并为治疗这种致命疾病提供了一种潜在的药理学策略。
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引用次数: 0
Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome. 抑制 GSK3α、β 可挽救 CTNNB1 综合征临床前小鼠模型的认知表型。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI: 10.1038/s44321-024-00110-5
Jonathan M Alexander, Leeanne Vazquez-Ramirez, Crystal Lin, Pantelis Antonoudiou, Jamie Maguire, Florence Wagner, Michele H Jacob

CTNNB1 syndrome is a rare monogenetic disorder caused by CTNNB1 de novo pathogenic heterozygous loss-of-function variants that result in cognitive and motor disabilities. Treatment is currently lacking; our study addresses this critical need. CTNNB1 encodes β-catenin which is essential for normal brain function via its dual roles in cadherin-based synaptic adhesion complexes and canonical Wnt signal transduction. We have generated a Ctnnb1 germline heterozygous mouse line that displays cognitive and motor deficits, resembling key features of CTNNB1 syndrome in humans. Compared with wild-type littermates, Ctnnb1 heterozygous mice also exhibit decreases in brain β-catenin, β-catenin association with N-cadherin, Wnt target gene expression, and Na/K ATPases, key regulators of changes in ion gradients during high activity. Consistently, hippocampal neuron functional properties and excitability are altered. Most important, we identify a highly selective inhibitor of glycogen synthase kinase (GSK)3α,β that significantly normalizes the phenotypes to closely meet wild-type littermate levels. Our data provide new insights into brain molecular and functional changes, and the first evidence for an efficacious treatment with therapeutic potential for individuals with CTNNB1 syndrome.

CTNNB1 综合征是一种罕见的单基因遗传性疾病,由 CTNNB1 新生致病性杂合子功能缺失变异引起,导致认知和运动障碍。目前尚缺乏治疗方法;我们的研究满足了这一关键需求。CTNNB1编码β-catenin,β-catenin在基于粘附蛋白的突触粘附复合物和典型Wnt信号转导中发挥双重作用,对正常脑功能至关重要。我们培育了一个 Ctnnb1 种系杂合子小鼠品系,该品系表现出认知和运动障碍,类似于人类 CTNNB1 综合征的主要特征。与野生型同系小鼠相比,Ctnnb1杂合子小鼠的大脑β-catenin、β-catenin与N-cadherin的关联、Wnt靶基因表达以及高活动时离子梯度变化的关键调控因子Na/K ATPases也出现下降。同样,海马神经元的功能特性和兴奋性也发生了改变。最重要的是,我们发现了一种糖原合酶激酶(GSK)3α、β的高选择性抑制剂,它能显著使表型正常化,接近野生型同胎鼠的水平。我们的数据为大脑分子和功能变化提供了新的视角,并首次证明了对 CTNNB1 综合征患者具有治疗潜力的有效治疗方法。
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引用次数: 0
Novel immunotherapeutics against LGR5 to target multiple cancer types. 针对多种癌症类型的 LGR5 新型免疫疗法。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-21 DOI: 10.1038/s44321-024-00121-2
Hung-Chang Chen, Nico Mueller, Katherine Stott, Chrysa Kapeni, Eilidh Rivers, Carolin M Sauer, Flavio Beke, Stephen J Walsh, Nicola Ashman, Louise O'Brien, Amir Rafati Fard, Arman Ghodsinia, Changtai Li, Fadwa Joud, Olivier Giger, Inti Zlobec, Ioana Olan, Sarah J Aitken, Matthew Hoare, Richard Mair, Eva Serrao, James D Brenton, Alicia Garcia-Gimenez, Simon E Richardson, Brian Huntly, David R Spring, Mikkel-Ole Skjoedt, Karsten Skjødt, Marc de la Roche, Maike de la Roche

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

我们开发并验证了一种针对人类 LGR5 细胞外结构域的高度特异性多功能抗体(α-LGR5)。α-LGR5能检测到90%以上的结直肠癌(CRC)、肝细胞癌(HCC)和前B-ALL肿瘤细胞中的LGR5过表达,并被用于生成抗体-药物共轭物(α-LGR5-ADC)、双特异性T细胞激活剂(α-LGR5-BiTE)和嵌合抗原受体(α-LGR5-CAR)。α-LGR5-ADC是体外靶向LGR5+癌细胞的最有效方式,并在人类NALM6前B-ALL小鼠模型中显示出强大的抗肿瘤疗效,使肿瘤损耗率低于对照治疗的1%。α-LGR5-CAR-T细胞在体外也显示出特异性和强效的LGR5+癌细胞杀伤力,并能有效靶向肿瘤,与对照组相比,前B-ALL肿瘤负荷减少了四倍。总之,我们的研究表明,α-LGR5 不仅可以作为一种研究工具和生物标记物,还能为针对一系列表达 LGR5 的癌细胞的高效免疫疗法组合提供一个通用的构件。
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引用次数: 0
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