Cell Reports MedicinePub Date : 2025-03-18Epub Date: 2025-03-07DOI: 10.1016/j.xcrm.2025.101996
Valdemar Brimnes Ingemann Johansen, Anna Katrina Jógvansdóttir Gradel, Stephanie Kjærulff Holm, Joyceline Cuenco, Christoffer Merrild, Natalia Petersen, Damien Demozay, Bharath Kumar Mani, Malte Palm Suppli, Magnus F G Grøndahl, Asger Bach Lund, Filip Krag Knop, Cesar A Prada-Medina, Wouter Frederik Johan Hogendorf, Jens Lykkesfeldt, Myrte Merkestein, Kei Sakamoto, Birgitte Holst, Christoffer Clemmensen
{"title":"Regulation of LEAP2 by insulin and glucagon in mice and humans.","authors":"Valdemar Brimnes Ingemann Johansen, Anna Katrina Jógvansdóttir Gradel, Stephanie Kjærulff Holm, Joyceline Cuenco, Christoffer Merrild, Natalia Petersen, Damien Demozay, Bharath Kumar Mani, Malte Palm Suppli, Magnus F G Grøndahl, Asger Bach Lund, Filip Krag Knop, Cesar A Prada-Medina, Wouter Frederik Johan Hogendorf, Jens Lykkesfeldt, Myrte Merkestein, Kei Sakamoto, Birgitte Holst, Christoffer Clemmensen","doi":"10.1016/j.xcrm.2025.101996","DOIUrl":"10.1016/j.xcrm.2025.101996","url":null,"abstract":"<p><p>Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous antagonist and inverse agonist of the ghrelin receptor, countering ghrelin's effects on cell signaling and feeding. However, despite an emerging interest in LEAP2's physiology and pharmacology, its endocrine regulation remains unclear. Here, we report that plasma LEAP2 levels decrease significantly upon glucagon infusions during somatostatin clamps in humans. This effect is preserved in patients with obesity and type 2 diabetes while diminished following a hypercaloric diet and a sedentary lifestyle for 2 weeks. Additionally, insulin receptor antagonism offsets the upregulation of LEAP2 during the postprandial state in mice. Finally, insulin and glucagon receptor-expressing hepatocytes are the primary source of hepatic LEAP2 expression, coinciding with a putative enhancer-like signature bound by insulin- and glucagon-regulated transcription factors at the LEAP2 locus. Collectively, our findings implicate insulin and glucagon in regulating LEAP2 and warrant further investigations into the exact mechanisms orchestrating this endocrine axis.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101996"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582220","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}
Cell Reports MedicinePub Date : 2025-03-18Epub Date: 2025-02-20DOI: 10.1016/j.xcrm.2025.101973
Christina Metoikidou, Vadim Karnaukhov, Bram Boeckx, Eleonora Timperi, Pierre-Emmanuel Bonté, Ling Wang, Marion Espenel, Benoit Albaud, Delphine Loirat, Xiaoxiao Wang, Christos Sotiriou, Philippe Aftimos, Kevin Punie, Hans Wildiers, Viktorija Labroska, Ming-Wei Wang, Joshua J Waterfall, Martine Piccart-Gebhart, Thierry Mora, Aleksandra Walczak, Olivier Lantz, Laurence Buisseret, Diether Lambrechts, Sebastian Amigorena, Emanuela Romano
{"title":"Continuous replenishment of the dysfunctional CD8 T cell axis is associated with response to chemoimmunotherapy in advanced breast cancer.","authors":"Christina Metoikidou, Vadim Karnaukhov, Bram Boeckx, Eleonora Timperi, Pierre-Emmanuel Bonté, Ling Wang, Marion Espenel, Benoit Albaud, Delphine Loirat, Xiaoxiao Wang, Christos Sotiriou, Philippe Aftimos, Kevin Punie, Hans Wildiers, Viktorija Labroska, Ming-Wei Wang, Joshua J Waterfall, Martine Piccart-Gebhart, Thierry Mora, Aleksandra Walczak, Olivier Lantz, Laurence Buisseret, Diether Lambrechts, Sebastian Amigorena, Emanuela Romano","doi":"10.1016/j.xcrm.2025.101973","DOIUrl":"10.1016/j.xcrm.2025.101973","url":null,"abstract":"<p><p>Chemotherapy combined with immune checkpoint blockade has shown clinical activity in breast cancer. Response, however, occurs in only a low proportion of patients. How the immune landscape of the tumor determines the immune and clinical responses to chemoimmunotherapy is not well understood. Here, using a combination of single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq), we profile 40 biopsies from 27 patients with metastatic triple-negative breast cancer (TNBC), receiving chemotherapy and anti-PD-L1 alone or in combination with anti-CD73, in a phase 2 randomized clinical trial. Our results show an enrichment of late-dysfunctional, clonally expanded CD8<sup>+</sup> T cells in responder (R) patients. On treatment, R display an influx of newly emerging clonotypes, as well as expansion of the CD8<sup>+</sup> precursors. Collectively, our data suggest that baseline clonal expansion could be a potential predictor of response and that both clonal reinvigoration of pre-existing tumor-reactive T cells and clonal replacement on-treatment are important for a protective response to chemoimmunotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101973"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472350","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":"Immune-featured stromal niches associate with response to neoadjuvant immunotherapy in oral squamous cell carcinoma.","authors":"Yu-Tong Liu, Hai-Ming Liu, Jian-Gang Ren, Wei Zhang, Xin-Xin Wang, Zi-Li Yu, Qiu-Yun Fu, Xue-Peng Xiong, Jun Jia, Bing Liu, Gang Chen","doi":"10.1016/j.xcrm.2025.102024","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102024","url":null,"abstract":"<p><p>Tumor stromal cells (TSCs) play a crucial yet underexplored role in the tumor microenvironment (TME). This study uses single-cell sequencing and spatial transcriptomics on paired tumor specimens from 22 patients with oral squamous cell carcinoma (OSCC) enrolled in a randomized two-arm phase 2 trial, receiving neoadjuvant anti-PD-1 mono-immunotherapy or anti-PD-1 plus docetaxel-cisplatin-5-fluorouracil (TPF) immunochemotherapy. Single-cell analysis reveals increased TSCs within the TME of responders in immunochemotherapy. Notably, significant post-treatment upregulation of SELP<sup>+</sup> high endothelial venules (HEVs) and APOD<sup>+</sup> myofibroblastic cancer-associated fibroblasts (myCAFs), alongside a decline in STMN1<sup>+</sup> capillary endothelial cells (cECs), is specific to the immunochemotherapy cohort. In contrast, MYF5<sup>+</sup> muscle satellite cells (MSCs) are upregulated in non-responders to mono-immunotherapy. SELP<sup>+</sup> HEVs and APOD<sup>+</sup> myCAFs foster favorable immunomodulatory stromal niches for improved outcomes, while STMN1<sup>+</sup> cECs and MYF5<sup>+</sup> MSCs form immunosuppressive niches in tumor invasion regions, highlighting therapeutic targets. The trial was registered at ClinicalTrials.gov, and the registration number is NCT04649476.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 3","pages":"102024"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662634","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":"BET inhibitor in combination with BCG vaccine enhances antitumor efficacy and orchestrates T cell reprogramming for melanoma.","authors":"Wenhua Wang, Xin Li, Rui Hu, Liang Dong, Shiyao Pei, Liping Jin, Qian Gao, Xiang Chen, Mingzhu Yin","doi":"10.1016/j.xcrm.2025.101995","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.101995","url":null,"abstract":"<p><p>Immunotherapy shows remarkable benefits in treating melanoma, yet existing approaches achieve limited overall responses. Here, we show that a combination of bromodomain and extra-terminal protein family inhibitor, NHWD-870, and Bacillus Calmette-Guérin vaccine is a promising therapeutic strategy for melanomas. Single-cell transcriptome analyses and functional experiments show that the combination therapy significantly inhibited tumor growth by reprogramming T cells toward an immune-activated state, enhancing their cytotoxicity, preventing their exhaustion, and increasing the recruitment of them into the tumor microenvironment. We identify the molecule, MT1, as a direct downstream target of BRD4, which is effectively suppressed by NHWD-870. Furthermore, our findings are reinforced by a humanized patient-derived xenograft (PDX) model, which exhibits notable antitumor effects in humanized tumor-bearing mice treated with the combination therapy. Our study underscores the immense potential of this therapeutic approach for clinical practice, offering promising prospects in overcoming the limitations of current treatments.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 3","pages":"101995"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662626","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}
Cell Reports MedicinePub Date : 2025-03-18Epub Date: 2025-03-03DOI: 10.1016/j.xcrm.2025.101989
Marco M Buttigieg, Caitlyn Vlasschaert, Alexander G Bick, Robert J Vanner, Michael J Rauh
{"title":"Inflammatory reprogramming of the solid tumor microenvironment by infiltrating clonal hematopoiesis is associated with adverse outcomes.","authors":"Marco M Buttigieg, Caitlyn Vlasschaert, Alexander G Bick, Robert J Vanner, Michael J Rauh","doi":"10.1016/j.xcrm.2025.101989","DOIUrl":"10.1016/j.xcrm.2025.101989","url":null,"abstract":"<p><p>Clonal hematopoiesis (CH)-the expansion of somatically mutated hematopoietic cells-is common in solid cancers. CH is associated with systemic inflammation, but its impact on tumor biology is underexplored. Here, we report the effects of CH on the tumor microenvironment (TME) using 1,550 treatment-naive patient samples from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) cohort. CH is present in 18.3% of patients, with one-third of CH mutations also detectable in tumor-derived DNA from the same individual (CH-Tum), reflecting CH-mutant leukocyte infiltration. Across cancers, the presence of CH-Tum is associated with worse survival outcomes. Molecular analyses reveal an association between CH-Tum and an immune-rich, inflammatory TME that is notably distinct from age-related gene expression changes. These effects are most prominent in glioblastoma, where CH correlates with pronounced macrophage infiltration, inflammation, and an aggressive, mesenchymal phenotype. Our findings demonstrate that CH shapes the TME, with potential applications as a biomarker in precision oncology.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101989"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556016","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}
Cell Reports MedicinePub Date : 2025-03-18Epub Date: 2025-02-22DOI: 10.1016/j.xcrm.2025.102026
Mercedes Guerrero-Murillo, Aina Rill-Hinarejos, Juan L Trincado, Alex Bataller, Valentín Ortiz-Maldonado, Daniel Benítez-Ribas, Marta Español-Rego, E Azucena González-Navarro, Nuria Martínez-Cibrián, Doménica Marchese, Lourdes Martín-Martín, Alejandro Martín García-Sancho, Susana Rives, Holger Heyn, Manel Juan, Álvaro Urbano-Ispizúa, Julio Delgado, Alberto Orfao, Elisabetta Mereu, Clara Bueno, Pablo Menendez
{"title":"Integrative single-cell multi-omics of CD19-CAR<sup>pos</sup> and CAR<sup>neg</sup> T cells suggest drivers of immunotherapy response in B cell neoplasias.","authors":"Mercedes Guerrero-Murillo, Aina Rill-Hinarejos, Juan L Trincado, Alex Bataller, Valentín Ortiz-Maldonado, Daniel Benítez-Ribas, Marta Español-Rego, E Azucena González-Navarro, Nuria Martínez-Cibrián, Doménica Marchese, Lourdes Martín-Martín, Alejandro Martín García-Sancho, Susana Rives, Holger Heyn, Manel Juan, Álvaro Urbano-Ispizúa, Julio Delgado, Alberto Orfao, Elisabetta Mereu, Clara Bueno, Pablo Menendez","doi":"10.1016/j.xcrm.2025.102026","DOIUrl":"10.1016/j.xcrm.2025.102026","url":null,"abstract":"","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102026"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482265","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}
Cell Reports MedicinePub Date : 2025-03-18Epub Date: 2025-02-24DOI: 10.1016/j.xcrm.2025.101978
Jingbo Wang, Xuemin Shen, Qifan Ma, Lin Yang, Xiaoyu Zhou, Luting Wang, Junqi Cui, Chunye Zhang, Guojun Li, Neil Gross, Siyi Li, Ruimin Huang, Changyou Zhan, Zhen Cheng, Kun Wang, Jie Tian, Ying Yuan, Xiaofeng Tao
{"title":"Near-infrared fluorescence imaging with an MET-targeting probe for biopsy site selection in patients with oral potentially malignant disorders.","authors":"Jingbo Wang, Xuemin Shen, Qifan Ma, Lin Yang, Xiaoyu Zhou, Luting Wang, Junqi Cui, Chunye Zhang, Guojun Li, Neil Gross, Siyi Li, Ruimin Huang, Changyou Zhan, Zhen Cheng, Kun Wang, Jie Tian, Ying Yuan, Xiaofeng Tao","doi":"10.1016/j.xcrm.2025.101978","DOIUrl":"10.1016/j.xcrm.2025.101978","url":null,"abstract":"<p><p>Accurate detection of malignant transformation in oral potentially malignant disorders (OPMDs) is crucial for guiding effective treatment and improving patient management. This study evaluates the potential of MET-binding peptide-indocyanine green (cMBP-ICG), a mesenchymal-epithelial transition factor (MET)-targeted near-infrared fluorescence imaging (NIRFI) probe, for biopsy site selection in OPMDs. Preclinical results demonstrate the superior accuracy of NIRFI-assisted biopsy over conventional oral examination (COE)-based biopsy in detecting high-grade dysplasia (HGD) or squamous cell carcinoma (SCC) and reducing missed detection rates. In a clinical trial with 50 patients, NIRFI-assisted biopsy achieves significantly higher diagnostic accuracy compared to COE-based biopsy (91% vs. 72%, p = 0.0005). These findings underscore the importance of NIRFI in enhancing diagnostic precision, supporting early detection and enabling timely and accurate treatment interventions for patients with OPMDs. The clinical trial is registered under the registration number ChiCTR2300074454.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101978"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499512","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":"Injectable hydrogel with miR-222-engineered extracellular vesicles ameliorates myocardial ischemic reperfusion injury via mechanotransduction.","authors":"Yongtao Wang, Danni Meng, Xiaohui Shi, Yan Hou, Shihui Zang, Lei Chen, Michail Spanos, Guoping Li, Dragos Cretoiu, Qiulian Zhou, Junjie Xiao","doi":"10.1016/j.xcrm.2025.101987","DOIUrl":"10.1016/j.xcrm.2025.101987","url":null,"abstract":"<p><p>Cardiac ischemic reperfusion injury (IRI) significantly exacerbates cardiac dysfunction and heart failure, causing high mortality. Despite the severity of IRI, effective therapeutic strategies remain elusive. Acellular cardiac patches have shown considerable efficacy in delivering therapeutics directly to cardiac tissues. Herein, we develop injectable GelMA (GEL) hydrogels with controlled mechanical properties. Targeting miR-222-engineered extracellular vesicles (TeEVs), tailored with cardiac-ischemia-targeting peptides (CTPs), are developed as ischemic TeEV therapeutics. These TeEVs are encapsulated within mechanical hydrogels to create injectable TeEV-loaded cardiac patches, enabling minimal invasiveness to attenuate IRI. The injectable patches facilitate the precise targeting of TeEVs for the efficient rescue of damaged cells. Persistent delivery of TeEVs into the infarcted region alleviates acute IRI and mitigated remodeling post IRI. This is linked to focal adhesion activation, cytoskeleton force enhancement, and nuclear force-sensing preservation. These findings may pave the way for force-sensing approaches to cardiac therapy using bioengineered therapeutic patches.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101987"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556018","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}
Cell Reports MedicinePub Date : 2025-03-18Epub Date: 2025-03-10DOI: 10.1016/j.xcrm.2025.102002
Jue Zhang, Diana Marcela Tabima, David Vereide, Weifeng Zeng, Nicholas J Albano, Sarah Lyon, Peter J Nicksic, Ellen C Shaffrey, Robert E George, Mitchell D Probasco, Elizabeth S Perrin, Yiyang Xu, Matthew E Brown, Ron Stewart, Naomi C Chesler, Lih-Sheng Turng, Samuel O Poore, Igor I Slukvin, James A Thomson, John P Maufort
{"title":"Small-diameter artery grafts engineered from pluripotent stem cells maintain 100% patency in an allogeneic rhesus macaque model.","authors":"Jue Zhang, Diana Marcela Tabima, David Vereide, Weifeng Zeng, Nicholas J Albano, Sarah Lyon, Peter J Nicksic, Ellen C Shaffrey, Robert E George, Mitchell D Probasco, Elizabeth S Perrin, Yiyang Xu, Matthew E Brown, Ron Stewart, Naomi C Chesler, Lih-Sheng Turng, Samuel O Poore, Igor I Slukvin, James A Thomson, John P Maufort","doi":"10.1016/j.xcrm.2025.102002","DOIUrl":"10.1016/j.xcrm.2025.102002","url":null,"abstract":"<p><p>Autologous vascular grafts, the only clinically approved option for small-diameter (<6 mm) revascularizations, require invasive harvesting and have limited availability and variable quality. To address these challenges, we develop a 3-mm-diameter artery graft by using arterial endothelial cells (AECs) derived from pluripotent stem cells (PSCs). After establishing technologies for pure AEC generation and expanded polytetrafluoroethylene (ePTFE) graft coating, we engineer artery grafts by seeding the inner lumen of ePTFE vascular grafts with either major histocompatibility complex (MHC) mismatched unmodified-wild-type (MHC-WT) AECs or MHC class I/II double knockout (MHC-DKO) AECs. Their function is evaluated in a rhesus arterial interposition grafting model. MHC-WT grafts maintained 100% patency for 6 months, significantly better than naked and MHC-DKO grafts. Additionally, the endothelium of MHC-WT grafts is repopulated with host cells, supporting long-term patency. Collectively, our study demonstrates that PSC-derived MHC-WT artery grafts provide an unlimited homogenous resource for allogeneic arterial revascularization.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102002"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604259","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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