{"title":"An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress.","authors":"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","doi":"10.1038/s44321-024-00132-z","DOIUrl":"https://doi.org/10.1038/s44321-024-00132-z","url":null,"abstract":"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.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"34 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233522","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}
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
{"title":"CRISPR-enabled point-of-care genotyping for APOL1 genetic risk assessment.","authors":"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","doi":"10.1038/s44321-024-00126-x","DOIUrl":"https://doi.org/10.1038/s44321-024-00126-x","url":null,"abstract":"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.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"12 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233520","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}
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
{"title":"A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death.","authors":"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","doi":"10.1038/s44321-024-00130-1","DOIUrl":"https://doi.org/10.1038/s44321-024-00130-1","url":null,"abstract":"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.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"10 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174785","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}
{"title":"Trained immunity of intestinal tuft cells during infancy enhances host defense against enteroviral infections in mice.","authors":"Deyan Chen,Jing Wu,Fang Zhang,Ruining Lyu,Qiao You,Yajie Qian,Yurong Cai,Xiaoyan Tian,Hongji Tao,Yating He,Waqas Nawaz,Zhiwei Wu","doi":"10.1038/s44321-024-00128-9","DOIUrl":"https://doi.org/10.1038/s44321-024-00128-9","url":null,"abstract":"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.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"149 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174643","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}
EMBO Molecular MedicinePub Date : 2024-09-01Epub Date: 2024-07-30DOI: 10.1038/s44321-024-00109-y
Salie Maasewerd, Bernardo Simoes Franklin
{"title":"\"Cruising together\"-ASC specks and SAA, a perfect match in chronic inflammation.","authors":"Salie Maasewerd, Bernardo Simoes Franklin","doi":"10.1038/s44321-024-00109-y","DOIUrl":"10.1038/s44321-024-00109-y","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1983-1985"},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855151","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}
{"title":"The RhoB p.S73F mutation leads to cerebral palsy through dysregulation of lipid homeostasis.","authors":"Xinyu Wu, Ruonan Liu, Zhongtian Zhang, Jie Yang, Xin Liu, Liqiang Jiang, Mengmeng Fang, Shoutang Wang, Liangxue Lai, Yuning Song, Zhanjun Li","doi":"10.1038/s44321-024-00113-2","DOIUrl":"10.1038/s44321-024-00113-2","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2002-2023"},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855153","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 : 2024-09-01Epub Date: 2024-08-15DOI: 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
{"title":"Histidine-rich glycoprotein modulates neutrophils and thrombolysis-associated hemorrhagic transformation.","authors":"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","doi":"10.1038/s44321-024-00117-y","DOIUrl":"10.1038/s44321-024-00117-y","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2146-2169"},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987659","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 : 2024-09-01Epub Date: 2024-07-31DOI: 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
{"title":"Therapeutic targeting ERRγ suppresses metastasis via extracellular matrix remodeling in small cell lung cancer.","authors":"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","doi":"10.1038/s44321-024-00108-z","DOIUrl":"10.1038/s44321-024-00108-z","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2043-2059"},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859283","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 : 2024-09-01Epub Date: 2024-08-09DOI: 10.1038/s44321-024-00102-5
Peiyong Guan, Jianfeng Chen, Chengqiang Mo, Tomoya Fukawa, Chao Zhang, Xiuyu Cai, Mei Li, Jing Han Hong, Jason Yongsheng Chan, Cedric Chuan Young Ng, Jing Yi Lee, Suet Far Wong, Wei Liu, Xian Zeng, Peili Wang, Rong Xiao, Vikneswari Rajasegaran, Swe Swe Myint, Abner Ming Sun Lim, Joe Poh Sheng Yeong, Puay Hoon Tan, Choon Kiat Ong, Tao Xu, Yiqing Du, Fan Bai, Xin Yao, Bin Tean Teh, Jing Tan
{"title":"Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability.","authors":"Peiyong Guan, Jianfeng Chen, Chengqiang Mo, Tomoya Fukawa, Chao Zhang, Xiuyu Cai, Mei Li, Jing Han Hong, Jason Yongsheng Chan, Cedric Chuan Young Ng, Jing Yi Lee, Suet Far Wong, Wei Liu, Xian Zeng, Peili Wang, Rong Xiao, Vikneswari Rajasegaran, Swe Swe Myint, Abner Ming Sun Lim, Joe Poh Sheng Yeong, Puay Hoon Tan, Choon Kiat Ong, Tao Xu, Yiqing Du, Fan Bai, Xin Yao, Bin Tean Teh, Jing Tan","doi":"10.1038/s44321-024-00102-5","DOIUrl":"10.1038/s44321-024-00102-5","url":null,"abstract":"<p><p>Collecting duct carcinoma (CDC) is an aggressive rare subtype of kidney cancer with unmet clinical needs. Little is known about its underlying molecular alterations and etiology, primarily due to its rarity, and lack of preclinical models. This study aims to comprehensively characterize molecular alterations in CDC and identify its therapeutic vulnerabilities. Through whole-exome and transcriptome sequencing, we identified KRAS hotspot mutations (G12A/D/V) in 3/13 (23%) of the patients, in addition to known TP53, NF2 mutations. 3/13 (23%) patients carried a mutational signature (SBS22) caused by aristolochic acid (AA) exposures, known to be more prevalent in Asia, highlighting a geologically specific disease etiology. We further discovered that cell cycle-related pathways were the most predominantly dysregulated pathways. Our drug screening with our newly established CDC preclinical models identified a CDK9 inhibitor LDC000067 that specifically inhibited CDC tumor growth and prolonged survival. Our study not only improved our understanding of oncogenic molecular alterations of Asian CDC, but also identified cell-cycle machinery as a therapeutic vulnerability, laying the foundation for clinical trials to treat patients with such aggressive cancer.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2132-2145"},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912240","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 : 2024-09-01Epub Date: 2024-08-21DOI: 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
{"title":"Novel immunotherapeutics against LGR5 to target multiple cancer types.","authors":"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","doi":"10.1038/s44321-024-00121-2","DOIUrl":"10.1038/s44321-024-00121-2","url":null,"abstract":"<p><p>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<sup>+</sup> 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<sup>+</sup> 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.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2233-2261"},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016725","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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