EMBO Molecular Medicine最新文献

Intramuscular self-amplifying RNA and adenoviral RSV vaccines program distinct systemic and respiratory mucosal immune architectures. 肌内自扩增RNA和腺病毒RSV疫苗规划不同的系统和呼吸粘膜免疫结构。

IF 7.9 1区医学

EMBO Molecular Medicine Pub Date : 2026-10-20 DOI: 10.1038/s44321-026-00537-y

Yao Zhang, Yu Qin, Zhongbing Qi, Qingzhe Yang, Xian Zhang, Shichuan Hu, Yuejun Li, Boduan Xiao, Jianchuan Hu, Ping Cheng

{"title":"Intramuscular self-amplifying RNA and adenoviral RSV vaccines program distinct systemic and respiratory mucosal immune architectures.","authors":"Yao Zhang, Yu Qin, Zhongbing Qi, Qingzhe Yang, Xian Zhang, Shichuan Hu, Yuejun Li, Boduan Xiao, Jianchuan Hu, Ping Cheng","doi":"10.1038/s44321-026-00537-y","DOIUrl":"https://doi.org/10.1038/s44321-026-00537-y","url":null,"abstract":"Respiratory syncytial virus (RSV) remains a major cause of severe lower respiratory tract disease in infants, older adults, and immunocompromised individuals, underscoring the need for vaccine strategies that balance systemic protection with frontline respiratory immunity. Although adenoviral and RNA-based RSV are both promising platforms, how the platform itself shapes systemic versus respiratory mucosal immunity under the same antigenic context remains insufficiently defined. We conducted a head-to-head comparison of an LNP-delivered saRNA vaccine (LNP-RSV-preF saRNA) and a recombinant Ad5-vectored vaccine (Ad5-RSV-preF) in mice using intramuscular prime-boost immunization. The two platforms drove distinct immune architectures rather than just differences in response magnitude. LNP-RSV-preF saRNA preferentially promoted respiratory mucosal immunity, including elevated BALF IgG, pulmonary antibody-secreting cells, CD69+ T cells, and lung-resident memory T (TRM) cells, as well as cycling and memory-associated CD8+ T-cell states and durable lung IgA memory. In contrast, Ad5-RSV-preF induced stronger systemic immunity, featured by higher early serum IgG, splenic polyfunctional effector T cells, enhanced germinal center/TFH responses, and effector-polarized CD8 + T cells, with sustained systemic humoral memory. Ad5-vectored and LNP-saRNA vaccine platforms induce distinct compartmentalized immune responses to the same RSV preF antigen. This study establishes a framework for rational platform selection in RSV vaccine design, enabling tailored strategies to balance systemic immunity and respiratory mucosal memory.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227568","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}

引用次数: 0

Spatial polarization of endothelial ICAM-1 governs T-cell exclusion in melanoma. 内皮细胞ICAM-1的空间极化控制黑色素瘤中t细胞的排斥。

IF 7.9 1区医学

EMBO Molecular Medicine Pub Date : 2026-10-19 DOI: 10.1038/s44321-026-00542-1

Ha-Ram Park, Shawn J Kim, Nashat Zaman, Nika P Kozlov, Somnath Tagore, Lawrence W Wu, Benjamin Izar, Minah Kim

{"title":"Spatial polarization of endothelial ICAM-1 governs T-cell exclusion in melanoma.","authors":"Ha-Ram Park, Shawn J Kim, Nashat Zaman, Nika P Kozlov, Somnath Tagore, Lawrence W Wu, Benjamin Izar, Minah Kim","doi":"10.1038/s44321-026-00542-1","DOIUrl":"https://doi.org/10.1038/s44321-026-00542-1","url":null,"abstract":"An immunosuppressive microenvironment limits therapeutic efficacy in melanoma. Beyond T-cell abundance and function, tumor control depends on T-cell access to malignant cells, yet the vascular mechanisms governing T-cell positioning remain poorly defined. Using RNA sequencing of endothelial cells from tumor cores versus peripheries in a mouse melanoma model, we identified intercellular adhesion molecule-1 (ICAM-1) as a candidate regulator of T-cell localization. During tumor growth, T cells shifted from a balanced core-margin distribution to marked exclusion from the core, particularly in T cell-inflamed tumors. This spatial polarization, less evident in other immune subsets, coincided with high expression of lymphocyte function-associated antigen-1 (LFA-1) on T cells. Endothelial ICAM-1 became enriched at the tumor periphery, where vascular integrity was compromised, with increased vascular leakage and reduced pericyte coverage. ICAM-1 blockade restored T-cell infiltration, enhanced effector activity, and delayed growth of immunogenic tumors, and sensitized an immune-refractory tumor to anti-PD-1 blockade. These findings identify endothelial ICAM-1 as a vascular determinant of T-cell positioning and the ICAM-1/LFA-1 axis as a modifiable checkpoint to enhance antitumor immunity and immunotherapy efficacy.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223565","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}

引用次数: 0

PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia. pten缺失导致t细胞急性淋巴细胞白血病依赖鸟苷酸合成酶IMPDH。

IF 7.9 1区医学

EMBO Molecular Medicine Pub Date : 2026-10-15 DOI: 10.1038/s44321-026-00533-2

Rayees A Padder, Thu Le Le, Emily Hyde, Maria E D Rubio, Eric Chiles, Jay N Joshi, Nanda Singh, Masuda Akther, Namratha Sheshadri, Kelly Mulraney, Wei-Xing Zong, Xiaoyang Su, Daniel Herranz, Alexander J Valvezan

{"title":"PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia.","authors":"Rayees A Padder, Thu Le Le, Emily Hyde, Maria E D Rubio, Eric Chiles, Jay N Joshi, Nanda Singh, Masuda Akther, Namratha Sheshadri, Kelly Mulraney, Wei-Xing Zong, Xiaoyang Su, Daniel Herranz, Alexander J Valvezan","doi":"10.1038/s44321-026-00533-2","DOIUrl":"10.1038/s44321-026-00533-2","url":null,"abstract":"Loss of the tumor suppressor PTEN is common in T-cell acute lymphoblastic leukemia (T-ALL) and is associated with poor prognosis. PTEN-loss drives AKT/mTORC1 signaling to promote leukemic cell growth. We find that PTEN-loss in T-ALL confers dependence on the guanylate nucleotide synthesis enzyme inosine 5'-monophosphate dehydrogenase (IMPDH) for cell growth and viability. This metabolic vulnerability is dependent on sustained AKT/mTORC1 signaling and can be exploited using clinically approved IMPDH inhibitors to selectively kill PTEN-deficient T-ALL cells, and extend survival in genetic and xenograft T-ALL models in mice. Mechanistically, IMPDH inhibitors cause DNA replication stress early on, followed by DNA damage. In contrast to treatment with mTORC1 inhibitors, these events culminate in robust and selective cell death in PTEN-deficient T-ALL cells. We also find that p53 enhances, but is not required for, IMPDH inhibitor-induced cell death. These findings reveal a targetable metabolic vulnerability in T-ALL, providing rationale for repurposing clinically approved IMPDH inhibitors.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149192157","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}

引用次数: 0

RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo. RMND1功能障碍导致体内OXPHOS缺乏并改变线粒体蛋白稳态。

IF 7.9 1区医学

EMBO Molecular Medicine Pub Date : 2026-10-14 DOI: 10.1038/s44321-026-00534-1

Alba Pesini, Maria J Sanchez-Quintero, Carlos Lopez-Gomez, Eliana Barriocanal-Casado, Agustin Hidalgo-Gutierrez, Eva Nyvltova, Joanna Rorbach, Giulio Kleiner, May T Ting, Christian Garcia, Lucia Dec-Prat, Kurenai Tanji, Christopher B Damoci, Robert McFarland, Robert W Taylor, Michal Minczuk, Antoni Barrientos, Catarina M Quinzii

{"title":"RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo.","authors":"Alba Pesini, Maria J Sanchez-Quintero, Carlos Lopez-Gomez, Eliana Barriocanal-Casado, Agustin Hidalgo-Gutierrez, Eva Nyvltova, Joanna Rorbach, Giulio Kleiner, May T Ting, Christian Garcia, Lucia Dec-Prat, Kurenai Tanji, Christopher B Damoci, Robert McFarland, Robert W Taylor, Michal Minczuk, Antoni Barrientos, Catarina M Quinzii","doi":"10.1038/s44321-026-00534-1","DOIUrl":"https://doi.org/10.1038/s44321-026-00534-1","url":null,"abstract":"Pathogenic, bi-allelic variants in RMND1 typically manifest as an early-onset multisystemic mitochondrial disease, yet the consequences of RMND1 dysfunction in vivo remain poorly understood. To answer this question, we generated and characterized the first in vivo model of RMND1-related disease, carrying the recurrent p.(Asn238Ser) variant. Homozygous Rmnd1N238S mice exhibit growth defect, premature mortality, and a multisystem phenotype marked by widespread tissue-dependent defects in oxidative phosphorylation assembly and activity. Quantitative proteomic analysis of Rmnd1N238S heart revealed extensive metabolic remodeling, with significant alterations in the abundance of mitoribosomal proteins and factors associated with mitoribosome maturation. Selected changes in mitoribosomal protein abundance were also observed in Rmnd1N238S liver, and RMND1 mutant and depleted human cells. Despite these changes, sucrose-gradient sedimentation did not reveal a gross alteration in mtSSU, mtLSU, or 55S distribution, suggesting that RMND1 dysfunction perturbs mitoribosomal protein homeostasis that could affect late-assembly stages of the mitochondrial ribosome large subunit. Together, our findings establish Rmnd1N238S mice as a robust in vivo model of RMND1-related disease and provide a framework for understanding how RMND1 supports mitochondrial gene expression.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180038","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}

引用次数: 0

Artificial intelligence in central nervous system autoimmune diseases: from clinical decision support to mechanistic discovery and translation. 人工智能在中枢神经系统自身免疫性疾病中的应用：从临床决策支持到机制发现和翻译。

IF 7.9 1区医学

EMBO Molecular Medicine Pub Date : 2026-10-13 DOI: 10.1038/s44321-026-00527-0

Zijian Cao, Pei Zheng, Zhihui Qi, Yang Yao, Donglin Xie, Yazi He, Shenghua Zong, Zongjiu Zhang, Fu-Dong Shi

{"title":"Artificial intelligence in central nervous system autoimmune diseases: from clinical decision support to mechanistic discovery and translation.","authors":"Zijian Cao, Pei Zheng, Zhihui Qi, Yang Yao, Donglin Xie, Yazi He, Shenghua Zong, Zongjiu Zhang, Fu-Dong Shi","doi":"10.1038/s44321-026-00527-0","DOIUrl":"https://doi.org/10.1038/s44321-026-00527-0","url":null,"abstract":"Central nervous system (CNS) autoimmune diseases, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), autoimmune encephalitis (AE), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), remain difficult to diagnose, stratify, and treat because clinical phenotypes overlap, biomarkers are imperfect, and the disease course requires longitudinal observation. Artificial intelligence (AI) is increasingly being evaluated to integrate clinical, imaging, immunological, and molecular data for decision-making in neuroimmunology. Clinical applications include automated neuroimaging analysis, differential diagnosis, disease classification, relapse prediction, prognostic stratification, and risk-informed care planning. Evidence is unevenly distributed: MS has the largest body of published work, particularly in neuroimaging, whereas studies in NMOSD, AE, and MOGAD are smaller, more heterogeneous, and often lack external validation. Computational approaches are also being applied to multi-omics, single-cell and spatial data, molecular target prioritisation, drug repositioning, trial enrichment, digital biomarkers, federated learning, and longitudinal modelling; however, these applications generally provide association, prioritisation, or hypothesis-generating evidence rather than validated therapeutic benefit. This Review maps reported applications, evidence patterns, and methodological and implementation needs rather than ranking translational maturity or implying established clinical benefit.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180084","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}

引用次数: 0

FDXR upregulation by p63/p73 is a prognostic and therapeutic marker of adult T-cell leukemia/lymphoma. p63/p73对FDXR的上调是成人t细胞白血病/淋巴瘤的预后和治疗标志物。

IF 7.9 1区医学

EMBO Molecular Medicine Pub Date : 2026-10-12 DOI: 10.1038/s44321-026-00535-0

Lara Gallucci, Maria Josephine, Yasunori Kogure, Alex Ap Rosini Silva, Vincent Cantaloube-Ferrieu, Marcos Eduardo Souza Abreu, Trusha Ramteke, Phoebe Kibble, Guilherme Lucchesi D Angelo Braz, Rubens de Assis Santos Sebastião, Luiza Amoroso Lambaz, Aijun Lin, Beth Hoare, Felipe Custódio Carvalho Dos Santos, Sophie Shackley, Alex Quin, Sofia Luari Moelas Giuzio, Philip A Lewis, Wujuan Zhang, Youko Nukui, Juliana Pereira, Hebert Fabricio Culler, Takuro Kameda, Kazuya Shimoda, Kate Heesom, Aaron R Goldman, Ester Cerdeira Sabino, Seishi Ogawa, Fabio Eudes Leal, Mattia Forcato, Keisuke Kataoka, Sheila de Oliveira Garcia Mateos, Iart Luca Shytaj

{"title":"FDXR upregulation by p63/p73 is a prognostic and therapeutic marker of adult T-cell leukemia/lymphoma.","authors":"Lara Gallucci, Maria Josephine, Yasunori Kogure, Alex Ap Rosini Silva, Vincent Cantaloube-Ferrieu, Marcos Eduardo Souza Abreu, Trusha Ramteke, Phoebe Kibble, Guilherme Lucchesi D Angelo Braz, Rubens de Assis Santos Sebastião, Luiza Amoroso Lambaz, Aijun Lin, Beth Hoare, Felipe Custódio Carvalho Dos Santos, Sophie Shackley, Alex Quin, Sofia Luari Moelas Giuzio, Philip A Lewis, Wujuan Zhang, Youko Nukui, Juliana Pereira, Hebert Fabricio Culler, Takuro Kameda, Kazuya Shimoda, Kate Heesom, Aaron R Goldman, Ester Cerdeira Sabino, Seishi Ogawa, Fabio Eudes Leal, Mattia Forcato, Keisuke Kataoka, Sheila de Oliveira Garcia Mateos, Iart Luca Shytaj","doi":"10.1038/s44321-026-00535-0","DOIUrl":"https://doi.org/10.1038/s44321-026-00535-0","url":null,"abstract":"Infection with HTLV-1 can lead to severe diseases, including adult T-cell leukemia/lymphoma (ATL), for which current therapies are inadequate. Selective elimination of chronically infected cells requires identifying cellular markers dysregulated by HTLV-1 that can be exploited therapeutically. Combining metabolomics and proteomics analyses, we identified increased expression of the mitochondrial enzyme ferredoxin reductase (FDXR) as a hallmark of HTLV-1-infected cells. In patient cells, FDXR upregulation mirrored disease severity, was enriched in proliferating tumour cells and predicted worse ATL prognosis. Mechanistically, FDXR upregulation in ATL cells is driven by the transactivating isoforms of two p53 family members, TAp63 and TAp73, and TAp63 expression is, in turn, induced by the IRF4/BATF3 transcriptional axis. In silico drug susceptibility predictions, followed by targeted cytotoxicity, proliferation and Drug-Seq assays demonstrated that FDXR upregulation is associated with increased sensitivity of ATL cells to repurposed chemotherapeutic agents, particularly fluorouracil. Overall, our findings establish FDXR as a novel biomarker of HTLV-1-associated disease progression and ATL prognosis, elucidate its upstream molecular regulation, and highlight its predictive potential for chemotherapeutic sensitivity of ATL cells.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166440","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}

引用次数: 0

Spatiotemporal heterologous vaccination relies on type I interferons at priming to enhance mucosal immunity. 时空异源疫苗接种依赖于I型干扰素在启动时增强粘膜免疫。

IF 7.9 1区医学

EMBO Molecular Medicine Pub Date : 2026-10-12 DOI: 10.1038/s44321-026-00539-w

Matthew J Wiest, Gabriel Laghlali, Julianne d'Acunzo, Chinghan Chung, Dilara Karadag, Vivian Yan, Seok-Chan Park, Moataz Noureddine, Katarzyna W Janczak, Chun Chen, Mohammad Farazuddin, Jessica J O'Konek, Adolfo García-Sastre, James R Baker, Michael Schotsaert, Pamela T Wong

{"title":"Spatiotemporal heterologous vaccination relies on type I interferons at priming to enhance mucosal immunity.","authors":"Matthew J Wiest, Gabriel Laghlali, Julianne d'Acunzo, Chinghan Chung, Dilara Karadag, Vivian Yan, Seok-Chan Park, Moataz Noureddine, Katarzyna W Janczak, Chun Chen, Mohammad Farazuddin, Jessica J O'Konek, Adolfo García-Sastre, James R Baker, Michael Schotsaert, Pamela T Wong","doi":"10.1038/s44321-026-00539-w","DOIUrl":"https://doi.org/10.1038/s44321-026-00539-w","url":null,"abstract":"Parenteral vaccines against respiratory viruses poorly block infection and transmission due to suboptimal induction of mucosal immunity. In contrast, hybrid immunity and heterologous-route immunization regimens generate protective mucosal and systemic immunity. Herein, we examine how chronological order in heterologous prime/boost immunization regimens impacts immune responses using combinations of intramuscular mRNA and intranasal adjuvanted subunit vaccines against SARS-CoV-2. Enhanced long-lived mucosal and systemic immunity depended strongly on vaccine delivery sequence, with heterologous regimens administered in alternate order of routes yielding markedly distinct immune profiles with different Th-biases and divergent localizations. Immunity imparted through heterologous immunization was more durable and responsive to delayed boosting than parenteral-only regimens. Furthermore, intramuscular mRNA immunization uniquely shaped gene expression locally and systemically through IFN-I induction, allowing for enhanced responses to subsequent mucosal immunizations. These findings demonstrate that the context of initial antigen exposure-including the route of exposure and associated inflammatory signals-profoundly shapes responses to subsequent encounters. Thus, vaccine responses in antigen-experienced hosts differ fundamentally from those induced on a naive baseline, reflecting the influence of pre-existing innate and adaptive immune memory.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166098","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}

引用次数: 0

Activated protein C promotes hematopoietic stem and progenitor cell quiescence and engraftment. 活化蛋白C促进造血干细胞和祖细胞的静止和着床。

IF 7.9 1区医学

EMBO Molecular Medicine Pub Date : 2026-10-09 DOI: 10.1038/s44321-026-00529-y

Simon J Pöllmann, Marcel G E Rommel, Leal Oburoglu, Tanja Hirch, Fabiola Valdivia-Francia, Kah Mun Siow, Timon Menzi, Julia Ackva, Franziska Schenk, Matthias J Neeracher, Ataman Sendoel, Janine Reichenbach, E Camilla Forsberg, Ute Modlich

{"title":"Activated protein C promotes hematopoietic stem and progenitor cell quiescence and engraftment.","authors":"Simon J Pöllmann, Marcel G E Rommel, Leal Oburoglu, Tanja Hirch, Fabiola Valdivia-Francia, Kah Mun Siow, Timon Menzi, Julia Ackva, Franziska Schenk, Matthias J Neeracher, Ataman Sendoel, Janine Reichenbach, E Camilla Forsberg, Ute Modlich","doi":"10.1038/s44321-026-00529-y","DOIUrl":"https://doi.org/10.1038/s44321-026-00529-y","url":null,"abstract":"Hematopoietic stem cells (HSCs) are the definitive source of all blood cells and replenish them for life. The endothelial protein C receptor (EPCR) which signals via its coreceptor protease-activated receptor 1 (PAR1) is expressed on a subpopulation of highly quiescent HSCs with high engraftment potential after transplantation. We demonstrate that EPCR/PAR1 on human CD34+ hematopoietic stem and progenitor cells (HSPCs) can be activated by both thrombin (THR) and activated protein C (aPC), inducing distinct signaling. PAR1 activation by THR in HSPCs led to Ca2+ flux, phosphorylation of CREB and ERK1/2 and increased glycolysis. In contrast, aPC activated CREB and AKT, but not ERK1/2, Ca2+ flux or metabolic changes. Functionally, stimulation of human CD34+ cells with aPC decreased differentiation and enhanced clonogenic potential. aPC counteracted the enforced proliferation of HSPCs by interleukin 1α in vitro. Short stimulation of CD34+ cells with aPC enhanced their short-term serial engraftment in immunodeficient mice. Our findings identify aPC/PAR1 signaling as a key target supporting CD34+ HSPC maintenance, stress resistance and regeneration, while THR/PAR1 signaling has opposing effects.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149691","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}

引用次数: 0

Apc-deficient pituitary stem cells drive adamantinomatous craniopharyngioma through senescence-associated inflammation. apc缺陷型垂体干细胞通过衰老相关炎症驱动硬瘤性颅咽管瘤。

IF 7.9 1区医学

EMBO Molecular Medicine Pub Date : 2026-10-09 DOI: 10.1038/s44321-026-00525-2

James Blackburn, James G Nicholson, Laura Gomez-Corral, Jingyi Xue, Ashutosh Rai, Bryan Padraig Finn, Rachael J L Tan, Kalyana C Chakravarthi, Angelica Gualtieri, Charlotte L Hall, Gabor Czibik, Pinaki Dutta, Márta Korbonits, Federico Roncaroli, Shannon W Davis, Carles Gaston-Massuet

{"title":"Apc-deficient pituitary stem cells drive adamantinomatous craniopharyngioma through senescence-associated inflammation.","authors":"James Blackburn, James G Nicholson, Laura Gomez-Corral, Jingyi Xue, Ashutosh Rai, Bryan Padraig Finn, Rachael J L Tan, Kalyana C Chakravarthi, Angelica Gualtieri, Charlotte L Hall, Gabor Czibik, Pinaki Dutta, Márta Korbonits, Federico Roncaroli, Shannon W Davis, Carles Gaston-Massuet","doi":"10.1038/s44321-026-00525-2","DOIUrl":"https://doi.org/10.1038/s44321-026-00525-2","url":null,"abstract":"Adamantinomatous craniopharyngiomas (aCPs) are complex intracranial neoplasms that arise in the sellar and suprasellar region of the brain, affecting the endocrine and nervous systems, causing severe sequelae. Although most of aCPs are driven by somatic mutations in β-catenin (CTNNB1), some cases remain genetically unresolved. Here, we show that disruption of the Wnt-antagonist and tumour suppressor adenomatous polyposis coli (Apc) leads to pituitary tumours that present all classic molecular and histopathological hallmarks of aCPs. Mechanistically, we show that a hypomorphic allele of Apc leads to tumour development and that bi-allelic loss of Apc in the Sox2+ve pituitary stem cells can initiate aCP formation. Apc-driven tumour-initiating cells show a distinct transcriptional signature of p21-mediated senescence-associated secretory phenotype (SASP) with methylomic analyses revealing shared epigenetic alteration of SASP-like inflammatory programme across aCP subtypes. Our data demonstrate a causal role of disruption of Apc in driving aCPs, reinforcing the importance of genetic testing for mutations in APC in patients with aCP. Furthermore, our work highlights the need to screen patients with familial adenomatous polyposis (FAP) or the spectrum of APC-pathogenic syndromes for aCP development early in life.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147590","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}

引用次数: 0

A novel Torque teno virus qPCR assay reveals longitudinal viral load variability among non-immunosuppressed subjects. 一种新的Torque teno病毒qPCR检测揭示了非免疫抑制受试者的纵向病毒载量变异性。

IF 7.9 1区医学

EMBO Molecular Medicine Pub Date : 2026-10-08 DOI: 10.1038/s44321-026-00540-3

Lara Valder, Thomas G Grigore, Christian Schaaf, Quirin Bachmann, Lutz Renders, Samuel D Jeske, Marc Lütgehetmann, Sibylle Bierbaum, Hartmut Hengel, Christopher Dächert, Ulrike Protzer, Jochen M Wettengel

{"title":"A novel Torque teno virus qPCR assay reveals longitudinal viral load variability among non-immunosuppressed subjects.","authors":"Lara Valder, Thomas G Grigore, Christian Schaaf, Quirin Bachmann, Lutz Renders, Samuel D Jeske, Marc Lütgehetmann, Sibylle Bierbaum, Hartmut Hengel, Christopher Dächert, Ulrike Protzer, Jochen M Wettengel","doi":"10.1038/s44321-026-00540-3","DOIUrl":"https://doi.org/10.1038/s44321-026-00540-3","url":null,"abstract":"Torque teno virus (TTV) DNA is an emerging biomarker of the individual immune status with considerable potential for guiding immunosuppressive therapy. However, widespread clinical implementation has been hampered by the lack of standardized, high-throughput diagnostic assays and limited understanding of the physiological variability of TTV viral loads over time. Here, we developed and analytically validated a novel fully automated high-throughput quantitative PCR assay for standardized TTV-DNA measurement in routine diagnostics and large-scale clinical studies. The assay demonstrated high analytical sensitivity and specificity, with a limit of detection of 32.3 copies/ml. Using this platform, we performed longitudinal profiling of plasma and serum samples collected over up to 51 months from non-immunosuppressed individuals. We observed substantial inter- and intra-individual fluctuations in TTV-DNA levels in a subset of healthy subjects, revealing intrinsic biological variability independent of immunosuppressive therapy. These findings establish a robust platform for standardized TTV monitoring while demonstrating that longitudinal viral load dynamics must be interpreted in the context of natural biological variation. Our study provides an important framework for the clinical implementation of TTV-guided immune monitoring and the need for development of evidence-based thresholds for individualized immunosuppressive therapies.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135491","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}

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