Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-09DOI: 10.1016/j.xcrm.2024.101850
Alex L Roederer, Yi Cao, Kerri St Denis, Maegan L Sheehan, Chia Jung Li, Evan C Lam, David J Gregory, Mark C Poznansky, A John Iafrate, David H Canaday, Stefan Gravenstein, Wilfredo F Garcia-Beltran, Alejandro B Balazs
{"title":"Ongoing evolution of SARS-CoV-2 drives escape from mRNA vaccine-induced humoral immunity.","authors":"Alex L Roederer, Yi Cao, Kerri St Denis, Maegan L Sheehan, Chia Jung Li, Evan C Lam, David J Gregory, Mark C Poznansky, A John Iafrate, David H Canaday, Stefan Gravenstein, Wilfredo F Garcia-Beltran, Alejandro B Balazs","doi":"10.1016/j.xcrm.2024.101850","DOIUrl":"10.1016/j.xcrm.2024.101850","url":null,"abstract":"<p><p>With the onset of the COVID-19 pandemic 4 years ago, viral sequencing continues to document numerous individual mutations in the viral spike protein across many variants. To determine the ability of vaccine-mediated humoral immunity to combat continued SARS-CoV-2 evolution, we construct a comprehensive panel of pseudoviruses harboring each individual mutation spanning 4 years of the pandemic to understand the fitness cost and resistance benefits of each. These efforts identify numerous mutations that escape from vaccine-induced humoral immunity. Across 50 variants and 131 mutants we construct, we observe progressive loss of neutralization across variants, irrespective of vaccine doses, as well as increasing infectivity and ACE2 binding. Importantly, the recent XBB.1.5 booster significantly increases titers against most variants but not JN.1, KP.2, or KP.3. These findings demonstrate that variants continue to evade updated mRNA vaccines, highlighting the need for different approaches to control SARS-CoV-2 transmission.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101850"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806124","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-11-25DOI: 10.1016/j.xcrm.2024.101831
Jean-Philippe Guégan, Florent Peyraud, Bérengère Dadone-Montaudie, Diego Teyssonneau, Lola-Jade Palmieri, Emma Clot, Sophie Cousin, Guilhem Roubaud, Mathilde Cabart, Laura Leroy, Coriolan Lebreton, Christophe Rey, Oren Lara, Ophélie Odin, Maxime Brunet, Lucile Vanhersecke, Ezogelin Oflazoglu Gruyters, Ikbel Achour, Leila Belcaid, Sylvestre Le Moulec, Thomas Grellety, Alban Bessede, Antoine Italiano
{"title":"Analysis of PD1, LAG3, TIGIT, and TIM3 expression in human lung adenocarcinoma reveals a 25-gene signature predicting immunotherapy response.","authors":"Jean-Philippe Guégan, Florent Peyraud, Bérengère Dadone-Montaudie, Diego Teyssonneau, Lola-Jade Palmieri, Emma Clot, Sophie Cousin, Guilhem Roubaud, Mathilde Cabart, Laura Leroy, Coriolan Lebreton, Christophe Rey, Oren Lara, Ophélie Odin, Maxime Brunet, Lucile Vanhersecke, Ezogelin Oflazoglu Gruyters, Ikbel Achour, Leila Belcaid, Sylvestre Le Moulec, Thomas Grellety, Alban Bessede, Antoine Italiano","doi":"10.1016/j.xcrm.2024.101831","DOIUrl":"10.1016/j.xcrm.2024.101831","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have advanced the treatment of non-small cell lung cancer (NSCLC). This study evaluates the predictive value of CD8<sup>+</sup> T cell exhaustion in patients with lung adenocarcinoma treated with ICIs. By analyzing tumor samples from 166 patients through multiplex immunofluorescence, we quantify tumor-infiltrating lymphocytes (TILs) expressing exhaustion markers programmed cell death-1 (PD1), lymphocyte activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and T cell immunoglobulin and mucin domain 3 (TIM3). Their co-expression is associated with ICI resistance, irrespective of programmed cell death ligand-1 (PD-L1) status. We also identify a 25-gene signature indicative of CD8<sup>+</sup> T cell exhaustion with high predictive accuracy for ICI response. Validated using several datasets from various clinical trials, this signature accurately predicts ICI responsiveness. Our findings highlight T cell exhaustion's significance in lung adenocarcinoma responses to ICIs and suggest the 25-gene signature as a potential universal biomarker to reinforce precision medicine. This was registered under Clinical Trial registration number NCT02534649.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101831"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726417","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-09DOI: 10.1016/j.xcrm.2024.101852
Subhamoy Chakraborty, Utsav Sen, Kedwin Ventura, Vrinda Jethalia, Charles Coleman, Subhasree Sridhar, Avisek Banerjee, Hilal Ozakinci, Yazhini Mahendravarman, Konrad Snioch, Elisa de Stanchina, Misty D Shields, Lewis E Tomalin, Deniz Demircioglu, Theresa A Boyle, Anna Tocheva, Dan Hasson, Triparna Sen
{"title":"Lurbinectedin sensitizes PD-L1 blockade therapy by activating STING-IFN signaling in small-cell lung cancer.","authors":"Subhamoy Chakraborty, Utsav Sen, Kedwin Ventura, Vrinda Jethalia, Charles Coleman, Subhasree Sridhar, Avisek Banerjee, Hilal Ozakinci, Yazhini Mahendravarman, Konrad Snioch, Elisa de Stanchina, Misty D Shields, Lewis E Tomalin, Deniz Demircioglu, Theresa A Boyle, Anna Tocheva, Dan Hasson, Triparna Sen","doi":"10.1016/j.xcrm.2024.101852","DOIUrl":"10.1016/j.xcrm.2024.101852","url":null,"abstract":"<p><p>Lurbinectedin is an approved second-line treatment for small-cell lung cancer (SCLC). SCLC clinical trials combining lurbinectedin with PD-L1 blockade are currently ongoing. However, the immunomodulatory effects of lurbinectedin remain largely unknown. In this study, we demonstrate that lurbinectedin treatment activates the STING pathway, which increases interferon (IFN) signaling, pro-inflammatory chemokines, and major histocompatibility complex class I (MHC-I) in SCLC models. Lurbinectedin treatment augments the anti-tumor immune response of PD-L1 blockade with significant tumor regression in first-line and maintenance settings in SCLC mouse models. In vivo, lurbinectedin treatment increases CD8<sup>+</sup> T cells and M1 macrophages and decreases immunosuppressive M2 macrophages. STING and CD8 depletion reverses the anti-tumor response. Interestingly, our study shows that lurbinectedin treatment upregulates MHC-I/II genes and CD8 in SCLC clinical samples. We provide mechanistic insights into the effect of lurbinectedin on STING-mediated multimodal immune activation and demonstrate that lurbinectedin treatment represents a promising therapeutic strategy to potentiate the efficacy of immunotherapy in SCLC.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101852"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805991","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":"Development and validation of the utLIFE-PC algorithm for noninvasive detection of prostate cancer in urine: A prospective, observational study.","authors":"Sujun Han, Mingshuai Wang, Yong Wang, Junlong Wu, Zhaoxia Guo, Huina Wang, Ranlu Liu, Xiaofu Qiu, Linjun Hu, Jianbin Bi, Weigang Yan, Hengqing An, Gejun Zhang, Yi Zhi, Zhiyuan Chen, Libin Chen, Lei Liu, Huanqing Cheng, Shuaipeng Zhu, Meng Wang, Yanrui Zhang, Xiao Liu, Feng Lou, Shanbo Cao, Dingwei Ye, Yuanjie Niu, Nianzeng Xing","doi":"10.1016/j.xcrm.2024.101870","DOIUrl":"10.1016/j.xcrm.2024.101870","url":null,"abstract":"<p><p>Overbiopsy is a serious health issue in prostate cancer (PCa) diagnostics. We have developed a urine tumor DNA multidimensional bioinformatic algorithm, utLIFE, to avoid unnecessary biopsy. The objective is to recognize all or clinically significant PCa. Of the 801 participants recruited in our study, 630 are selected for subsequent analysis. In the training cohort (n = 237), utLIFE-PC gets an area under the receiver operating characteristic curve (AUC) of 0.967 and a sensitivity of 85.57% at 95% specificity. In the independent prospective validation cohort (n = 343), utLIFE-PC has an AUC of 0.929, sensitivity of 84.24%, and specificity of 93.26%. Notably, in patients with ≥grade group (GG)2 and ≥GG3, the assay's sensitivity is still excellent (85.33% and 87.10%, respectively). The model shows better performance than prostate-specific antigen (PSA) (p < 0.001) or the single-dimensional biomarkers (methylation, p < 0.001; copy-number variations [CNVs], p < 0.001; mutation, p < 0.001). The utLIFE-PC model can potentially optimize the PCa diagnostic process and avoid unnecessary biopsies. This study was registered at Chinese Clinical Trial Registry: ChiCTR2300071837.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101870"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805876","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-12DOI: 10.1016/j.xcrm.2024.101843
Xiangdong Li, Renjie Ding, Zhenhua Liu, Wilhem M S Teixeira, Jingwei Ye, Li Tian, Haojiang Li, Shengjie Guo, Kai Yao, Zikun Ma, Zhuowei Liu
{"title":"A predictive system comprising serum microRNAs and radiomics for residual retroperitoneal masses in metastatic nonseminomatous germ cell tumors.","authors":"Xiangdong Li, Renjie Ding, Zhenhua Liu, Wilhem M S Teixeira, Jingwei Ye, Li Tian, Haojiang Li, Shengjie Guo, Kai Yao, Zikun Ma, Zhuowei Liu","doi":"10.1016/j.xcrm.2024.101843","DOIUrl":"10.1016/j.xcrm.2024.101843","url":null,"abstract":"<p><p>Predicting the histopathology of residual retroperitoneal masses (RMMs) before post-chemotherapy retroperitoneal lymph node dissection in metastatic nonseminomatous germ cell tumors (NSGCTs) can guide individualized treatment and minimize complications. Previous single approach-based models perform poorly in validation. Herein, we introduce a machine learning model that evolves from a single-dimensional tumor diameter to incorporate high-dimensional radiomic features, with its effectiveness assessed using the macro-average area under the receiver operating characteristic curves (AUCs). In addition, we utilize more precise and specific microRNAs (miRNAs), not common clinical indicators, to construct an integrated radiomics-miRNA predictive system, achieving an AUC of 0.91 (0.80-0.99) in the prospective test set. We further develop a web-based dynamic nomogram for swift and precise calculation of the histopathological probabilities of RMMs based on radiomic scores and serum miRNA levels. The radiomics-miRNA integrated system offers a promising tool to select personalized treatments for patients with metastatic NSGCT.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101843"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821966","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":"Foundation model of ECG diagnosis: Diagnostics and explanations of any form and rhythm on ECG.","authors":"Yuanyuan Tian, Zhiyuan Li, Yanrui Jin, Mengxiao Wang, Xiaoyang Wei, Liqun Zhao, Yunqing Liu, Jinlei Liu, Chengliang Liu","doi":"10.1016/j.xcrm.2024.101875","DOIUrl":"10.1016/j.xcrm.2024.101875","url":null,"abstract":"<p><p>We propose a knowledge-enhanced electrocardiogram (ECG) diagnosis foundation model (KED) that utilizes large language models to incorporate domain-specific knowledge of ECG signals. This model is trained on 800,000 ECGs from nearly 160,000 unique patients. Despite being trained on single-center data, KED demonstrates exceptional zero-shot diagnosis performance across various regions, including different locales in China, the United States, and other regions. This performance spans across all age groups for various conditions such as morphological abnormalities, rhythm abnormalities, conduction blocks, hypertrophy, myocardial ischemia, and infarction. Moreover, KED exhibits robust performance on diseases it has not encountered during its training. When compared to three experienced cardiologists on real clinical datasets, the model achieves comparable performance in zero-shot diagnosis of seven common clinical ECG types. We concentrate on the zero-shot diagnostic capability and the generalization performance of the proposed ECG foundation model, particularly in the context of external multi-center data and previously unseen disease.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"5 12","pages":"101875"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853168","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}
Pietro Scilipoti, Marco Moschini, Alberto Briganti
{"title":"Reflections on the AMBASSADOR trial: The role of adjuvant pembrolizumab in muscle-invasive urothelial carcinoma.","authors":"Pietro Scilipoti, Marco Moschini, Alberto Briganti","doi":"10.1016/j.xcrm.2024.101873","DOIUrl":"10.1016/j.xcrm.2024.101873","url":null,"abstract":"<p><p>Recent advances in immunotherapy have transformed treatment for muscle-invasive urothelial carcinoma, providing hope for cisplatin-ineligible patients. The AMBASSADOR trial evaluated adjuvant pembrolizumab in high-risk patients post-surgery, demonstrating improved disease-free survival. As overall survival data evolve, pembrolizumab is emerging as a promising adjuvant treatment option, complementing existing therapies in the treatment landscape for this disease.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"5 12","pages":"101873"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853203","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-09DOI: 10.1016/j.xcrm.2024.101869
Xingying Zhang, Chenze Zhang, Shan Lu, Jingxi Dong, Na Tang, Yao Wang, Weidong Han, Xi Pan, Xiang Zhang, Duan Liu, Ng Shyh-Chang, Yu Wang, Guihai Feng, Haoyi Wang
{"title":"Miltefosine reinvigorates exhausted T cells by targeting their bioenergetic state.","authors":"Xingying Zhang, Chenze Zhang, Shan Lu, Jingxi Dong, Na Tang, Yao Wang, Weidong Han, Xi Pan, Xiang Zhang, Duan Liu, Ng Shyh-Chang, Yu Wang, Guihai Feng, Haoyi Wang","doi":"10.1016/j.xcrm.2024.101869","DOIUrl":"10.1016/j.xcrm.2024.101869","url":null,"abstract":"<p><p>T cell exhaustion presents a major challenge for the efficacy of both immune checkpoint inhibitors (ICBs) and chimeric antigen receptor T (CAR-T) cell immunotherapies. To address this issue, we generate hypofunctional CAR-T cells that imitate the exhaustion state. By screening a Food and Drug Administration (FDA)-approved small molecule library using this model, we identify miltefosine as a potent molecule that restores the impaired function of CAR-T cells in a PD-1/PD-L1-independent manner. Impressively, in the terminally exhausted state where PD-1 antibody treatment is ineffective, miltefosine still enhances CAR-T cell activity. Single-cell sequencing analysis reveals that miltefosine treatment significantly increases the population of effector cells. Mechanistically, miltefosine improves impaired glycolysis and oxidative phosphorylation in hypofunctional CAR-T cells. In both allogeneic and syngeneic tumor models, miltefosine effectively enhances the solid tumor clearance ability of CAR-T cells and T cells, demonstrating its potential as an effective immunotherapeutic drug.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101869"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806027","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-02DOI: 10.1016/j.xcrm.2024.101834
Sharad Awasthi, Lacey E Dobrolecki, Christina Sallas, Xudong Zhang, Yang Li, Sima Khazaei, Sumanta Ghosh, Collene R Jeter, Jinsong Liu, Gordon B Mills, Shannon N Westin, Michael T Lewis, Weiyi Peng, Anil K Sood, Timothy A Yap, S Stephen Yi, Daniel J McGrail, Nidhi Sahni
{"title":"UBA1 inhibition sensitizes cancer cells to PARP inhibitors.","authors":"Sharad Awasthi, Lacey E Dobrolecki, Christina Sallas, Xudong Zhang, Yang Li, Sima Khazaei, Sumanta Ghosh, Collene R Jeter, Jinsong Liu, Gordon B Mills, Shannon N Westin, Michael T Lewis, Weiyi Peng, Anil K Sood, Timothy A Yap, S Stephen Yi, Daniel J McGrail, Nidhi Sahni","doi":"10.1016/j.xcrm.2024.101834","DOIUrl":"10.1016/j.xcrm.2024.101834","url":null,"abstract":"<p><p>Therapeutic strategies targeting the DNA damage response, such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), have revolutionized cancer treatment in tumors deficient in homologous recombination (HR). However, overcoming innate and acquired resistance to PARPi remains a significant challenge. Here, we employ a genome-wide CRISPR knockout screen and discover that the depletion of ubiquitin-activating enzyme E1 (UBA1) enhances sensitivity to PARPi in HR-proficient ovarian cancer cells. We show that silencing or pharmacological inhibition of UBA1 sensitizes multiple cell lines and organoid models to PARPi. Mechanistic studies uncover that UBA1 inhibition not only impedes HR repair to sensitize cells to PARP inhibition but also increases PARylation, which may subsequently be targeted by PARP inhibition. In vivo experiments using patient-derived xenografts demonstrate that combining PARP and UBA1 inhibition provided significant survival benefit compared to individual therapies with no detectable signs of toxicity, establishing this combination approach as a promising strategy to extend PARPi benefit.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101834"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766730","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-02DOI: 10.1016/j.xcrm.2024.101832
Esra Karakose, Xuedi Wang, Peng Wang, Saul Carcamo, Deniz Demircioglu, Luca Lambertini, Olivia Wood, Randy Kang, Geming Lu, Donald K Scott, Adolfo Garcia-Ocaña, Carmen Argmann, Robert P Sebra, Dan Hasson, Andrew F Stewart
{"title":"Cycling alpha cells in regenerative drug-treated human pancreatic islets may serve as key beta cell progenitors.","authors":"Esra Karakose, Xuedi Wang, Peng Wang, Saul Carcamo, Deniz Demircioglu, Luca Lambertini, Olivia Wood, Randy Kang, Geming Lu, Donald K Scott, Adolfo Garcia-Ocaña, Carmen Argmann, Robert P Sebra, Dan Hasson, Andrew F Stewart","doi":"10.1016/j.xcrm.2024.101832","DOIUrl":"10.1016/j.xcrm.2024.101832","url":null,"abstract":"<p><p>Diabetes results from an inadequate number of insulin-producing human beta cells. There is currently no clinically available effective means to restore beta cell mass in millions of people with diabetes. Although the DYRK1A inhibitors, either alone or in combination with GLP-1 receptor agonists (GLP-1) or transforming growth factor β (TGF-β) superfamily inhibitors (LY), induce beta cell replication and increase beta cell mass, the precise mechanisms of action remain elusive. Here we perform single-cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone or with GLP-1 or LY. We identify cycling alpha cells as the most responsive cells to DYRK1A inhibition. Lineage trajectory analyses suggest that cycling alpha cells may serve as precursor cells that transdifferentiate into beta cells. Collectively, in addition to enhancing expression of beta cell phenotypic genes in beta cells, our findings suggest that regenerative drugs may be targeting cycling alpha cells in human islets.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101832"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766780","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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