Pub Date : 2026-03-11DOI: 10.1126/scitranslmed.adp2196
Rebecca Asiimwe,Brittney Knott,Morgan E Greene,Emma D Wright,Markayla Bell,Daniel Epstein,Stefani D Yates,Michael V Gonzalez,Samantha Fry,Emily Boydston Procópio,Stephanie Clevenger,Jayme E Locke,Brian E Brocato,Constantine M Burgan,Richard Burney,Nitin Arora,Virginia E Duncan,Holly E Richter,Deidre Gunn,Aharon G Freud,Shawn C Little,Paige M Porrett
Uterine natural killer (uNK) cells are a tissue-resident lymphocyte population critical for pregnancy success. Although mouse models have demonstrated that uNK cell deficiency results in abnormal placentation and poor pregnancy outcomes, the generalizability of this knowledge to humans remains unclear. Here, we compared tissue samples collected from a cohort of human recipients of uterus transplant (UTx) at high risk for pregnancy complications with healthy controls using flow cytometry, immunofluorescence microscopy, and single-cell RNA sequencing (scRNA-seq). Subsets of tissue-resident uNK cells were reduced in endometrial and decidual samples from recipients of UTx compared with healthy control samples. Loss of tissue-resident uNK cells was associated with histopathologic evidence of maternal vascular malperfusion in placentas from recipients of UTx and related pregnancy complications including preeclampsia. scRNA-seq of UTx endometrial biopsies and deciduae further revealed that the NK cell reduction in recipients of UTx correlated with impaired transcriptional programming of NK tissue residency arising from the inhibition of signaling by nuclear factor of activated T cells (NFAT). In vitro culture of uNK cells from healthy controls with the NFAT inhibitor tacrolimus resulted in down-regulation of adhesion molecules. Together, these experiments suggested that NFAT-dependent genes modulate multiple molecular tissue residency programs in uNK cells, including early residency programs involving activator protein-1 (AP-1) family transcription factors and later residency programs characterized by up-regulation of surface integrins by transforming growth factor-β (TGF-β). Collectively, these data identify a previously undescribed role for NFAT in uNK tissue residency and provide mechanistic insights into the biologic basis of pregnancy complications due to alteration of tissue-resident NK cell subsets in humans.
{"title":"Inhibition of NFAT after human uterus transplant promotes loss of tissue-resident NK cells and attendant pregnancy complications.","authors":"Rebecca Asiimwe,Brittney Knott,Morgan E Greene,Emma D Wright,Markayla Bell,Daniel Epstein,Stefani D Yates,Michael V Gonzalez,Samantha Fry,Emily Boydston Procópio,Stephanie Clevenger,Jayme E Locke,Brian E Brocato,Constantine M Burgan,Richard Burney,Nitin Arora,Virginia E Duncan,Holly E Richter,Deidre Gunn,Aharon G Freud,Shawn C Little,Paige M Porrett","doi":"10.1126/scitranslmed.adp2196","DOIUrl":"https://doi.org/10.1126/scitranslmed.adp2196","url":null,"abstract":"Uterine natural killer (uNK) cells are a tissue-resident lymphocyte population critical for pregnancy success. Although mouse models have demonstrated that uNK cell deficiency results in abnormal placentation and poor pregnancy outcomes, the generalizability of this knowledge to humans remains unclear. Here, we compared tissue samples collected from a cohort of human recipients of uterus transplant (UTx) at high risk for pregnancy complications with healthy controls using flow cytometry, immunofluorescence microscopy, and single-cell RNA sequencing (scRNA-seq). Subsets of tissue-resident uNK cells were reduced in endometrial and decidual samples from recipients of UTx compared with healthy control samples. Loss of tissue-resident uNK cells was associated with histopathologic evidence of maternal vascular malperfusion in placentas from recipients of UTx and related pregnancy complications including preeclampsia. scRNA-seq of UTx endometrial biopsies and deciduae further revealed that the NK cell reduction in recipients of UTx correlated with impaired transcriptional programming of NK tissue residency arising from the inhibition of signaling by nuclear factor of activated T cells (NFAT). In vitro culture of uNK cells from healthy controls with the NFAT inhibitor tacrolimus resulted in down-regulation of adhesion molecules. Together, these experiments suggested that NFAT-dependent genes modulate multiple molecular tissue residency programs in uNK cells, including early residency programs involving activator protein-1 (AP-1) family transcription factors and later residency programs characterized by up-regulation of surface integrins by transforming growth factor-β (TGF-β). Collectively, these data identify a previously undescribed role for NFAT in uNK tissue residency and provide mechanistic insights into the biologic basis of pregnancy complications due to alteration of tissue-resident NK cell subsets in humans.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"127 1","pages":"eadp2196"},"PeriodicalIF":17.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393962","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}
Pub Date : 2026-03-04DOI: 10.1126/scitranslmed.aea8770
Annie Dosey, Bernadeta Dadonaite, Rebecca A. Gillespie, Elizabeth M. Leaf, Matthew J. Vukovich, Jackson McGowan, Emily Grey, Hiromi Muramatsu, Rachel H. J. Jun, Norbert Pardi, Masaru Kanekiyo, Jesse D. Bloom, Neil P. King
Transmission of highly pathogenic avian influenza from H5 clade 2.3.4.4b has expanded in recent years to infect large populations of birds and mammals, heightening the risk of a human pandemic. Influenza viruses that are adapted to transmission in birds and a variety of mammals tend to have a less stable hemagglutinin (HA) than seasonal influenza viruses, enabling membrane fusion at comparatively higher pH levels. Here, we combined five mutations in the H5 HA that increased its melting temperature and promoted stable closure of the HA trimer. Structural analysis by cryo–electron microscopy revealed that the stabilizing mutations create several new hydrophobic interactions while maintaining the local HA structure. We found that vaccinating mice with stabilized H5 HA immunogens resulted in higher hemagglutination inhibition and neutralization titers than nonstabilized comparators. Epitope mapping of vaccine-elicited polyclonal antibody responses using negative-stain electron microscopy and deep mutational scanning showed that site E on the side of the HA receptor binding domain was immunodominant across all groups; however, the stabilized immunogens shifted responses toward the receptor binding site, which elicited a higher proportion of neutralizing antibodies. Consistent with these findings, stabilized H5 HA immunogens delivered as messenger RNA–lipid nanoparticle (mRNA-LNP) vaccines protected mice against H5N1 challenge. These findings highlight that H5 HA–stabilizing mutations enhance the quality of antibody responses across different vaccine formats, underscoring their potential to improve pandemic preparedness vaccines targeting viruses from this widely circulating clade.
{"title":"Stabilization of the H5 clade 2.3.4.4b hemagglutinin improves vaccine-elicited neutralizing antibody responses in mice","authors":"Annie Dosey, Bernadeta Dadonaite, Rebecca A. Gillespie, Elizabeth M. Leaf, Matthew J. Vukovich, Jackson McGowan, Emily Grey, Hiromi Muramatsu, Rachel H. J. Jun, Norbert Pardi, Masaru Kanekiyo, Jesse D. Bloom, Neil P. King","doi":"10.1126/scitranslmed.aea8770","DOIUrl":"https://doi.org/10.1126/scitranslmed.aea8770","url":null,"abstract":"Transmission of highly pathogenic avian influenza from H5 clade 2.3.4.4b has expanded in recent years to infect large populations of birds and mammals, heightening the risk of a human pandemic. Influenza viruses that are adapted to transmission in birds and a variety of mammals tend to have a less stable hemagglutinin (HA) than seasonal influenza viruses, enabling membrane fusion at comparatively higher pH levels. Here, we combined five mutations in the H5 HA that increased its melting temperature and promoted stable closure of the HA trimer. Structural analysis by cryo–electron microscopy revealed that the stabilizing mutations create several new hydrophobic interactions while maintaining the local HA structure. We found that vaccinating mice with stabilized H5 HA immunogens resulted in higher hemagglutination inhibition and neutralization titers than nonstabilized comparators. Epitope mapping of vaccine-elicited polyclonal antibody responses using negative-stain electron microscopy and deep mutational scanning showed that site E on the side of the HA receptor binding domain was immunodominant across all groups; however, the stabilized immunogens shifted responses toward the receptor binding site, which elicited a higher proportion of neutralizing antibodies. Consistent with these findings, stabilized H5 HA immunogens delivered as messenger RNA–lipid nanoparticle (mRNA-LNP) vaccines protected mice against H5N1 challenge. These findings highlight that H5 HA–stabilizing mutations enhance the quality of antibody responses across different vaccine formats, underscoring their potential to improve pandemic preparedness vaccines targeting viruses from this widely circulating clade.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"28 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147351031","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}
Pub Date : 2026-03-04DOI: 10.1126/scitranslmed.adw9286
Torahito A. Gao, Ryan M. Shih, Justin D. Clubb, Shao-Hsi Hung, Tanya Singh, Laura B. James-Allan, Gabriella DiBernardo, Amanda Shafer, Amber Bouren, Melanie Ayala Ceja, Sophie Ong, Andréa B. Ball, Ajit S. Divakaruni, Sanaz Memarzadeh, Han-Chung Wu, Yvonne Y. Chen
Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy against solid tumors, which often reside in highly immunosuppressive tumor microenvironments (TMEs). TMEs can be highly abundant in vascular endothelial growth factor A (VEGF), which contributes to immunosuppression and abnormal tumor vasculature. Here, we found that CAR T cells engineered to secrete an anti-VEGF single-chain variable fragment (CAR-αVEGF T cells) achieved superior antitumor efficacy against multiple in vivo models of ovarian cancer and glioma, outperforming conventional CAR T cells with and without combination anti-VEGF antibody therapy. Microscopy, flow cytometry, and transcriptomic analyses revealed that armoring the CAR T cells with anti-VEGF single-chain variable fragments enhanced their activation and mitochondrial fitness and enriched immune-stimulatory signatures among endogenous immune cells in the tumor-bearing brain. Moreover, CAR-αVEGF T cells circumvented multiple detrimental effects associated with on-target CAR T cell therapy, including infiltration of suppressive myeloid cells, exaggerated vasculature abnormalities, and hypoxia. Together, our results provide rationale for the clinical translation of CAR-αVEGF T cells as a safe and potent therapy for solid tumors characterized by elevated VEGF.
{"title":"Engineering CAR T cells to secrete VEGF-neutralizing scFvs enhances antitumor activity against solid tumors","authors":"Torahito A. Gao, Ryan M. Shih, Justin D. Clubb, Shao-Hsi Hung, Tanya Singh, Laura B. James-Allan, Gabriella DiBernardo, Amanda Shafer, Amber Bouren, Melanie Ayala Ceja, Sophie Ong, Andréa B. Ball, Ajit S. Divakaruni, Sanaz Memarzadeh, Han-Chung Wu, Yvonne Y. Chen","doi":"10.1126/scitranslmed.adw9286","DOIUrl":"https://doi.org/10.1126/scitranslmed.adw9286","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy against solid tumors, which often reside in highly immunosuppressive tumor microenvironments (TMEs). TMEs can be highly abundant in vascular endothelial growth factor A (VEGF), which contributes to immunosuppression and abnormal tumor vasculature. Here, we found that CAR T cells engineered to secrete an anti-VEGF single-chain variable fragment (CAR-αVEGF T cells) achieved superior antitumor efficacy against multiple in vivo models of ovarian cancer and glioma, outperforming conventional CAR T cells with and without combination anti-VEGF antibody therapy. Microscopy, flow cytometry, and transcriptomic analyses revealed that armoring the CAR T cells with anti-VEGF single-chain variable fragments enhanced their activation and mitochondrial fitness and enriched immune-stimulatory signatures among endogenous immune cells in the tumor-bearing brain. Moreover, CAR-αVEGF T cells circumvented multiple detrimental effects associated with on-target CAR T cell therapy, including infiltration of suppressive myeloid cells, exaggerated vasculature abnormalities, and hypoxia. Together, our results provide rationale for the clinical translation of CAR-αVEGF T cells as a safe and potent therapy for solid tumors characterized by elevated VEGF.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"53 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350632","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}
Gestational diabetes mellitus (GDM) can increase the risk for diabetes in offspring, but the mechanisms underlying the effects of intrauterine hyperglycemia (IHG) on the fetus remain unknown. Here, we show that IHG down-regulated DNA demethylases TET2/3 in fetal pancreatic islets, increased DNA methylation of γ-aminobutyric acid (GABA) synthesis gene Gad1 , suppressed Gad1 expression, and elevated somatostatin (SST) protein in the pancreas in mice. Pancreas-specific double knockout (DKO) of Tet2/3 recapitulates the IHG effects, causing Gad1 hypermethylation and expression down-regulation, alongside impaired insulin secretion and glucose tolerance. Metabolomic analysis revealed that IHG and Tet2/3 DKO reduced pancreatic GABA content. Gestational dietary GABA supplementation improved metabolic defects in both IHG and Tet2/3 DKO models. scRNA-seq analysis of pancreatic islets showed that IHG or Tet2/3 DKO down-regulated the β cell signature, whereas up-regulating δ cell–related genes, particularly Sst , led to the emergence of an Ins2/Sst double-positive cell population. β cell–specific deletion of Sst rescued IHG-induced metabolic defects. In humans, GDM was associated with reduced GABA content in the umbilical arterial blood. These results uncover an epigenetically controlled pancreatic GABA-SST signaling pathway that may contribute to the GDM-induced increase in offspring diabetes risk and identify dietary GABA supplementation as a potential interventional strategy.
{"title":"Epigenetically regulated pancreatic GABA-somatostatin signaling underlies gestational diabetes–induced glucose intolerance in offspring","authors":"Hong Zhu, Sisi Luo, Cenxi Liu, Yi Cheng, Zhuoran Ren, Jiahang Mo, Chong Cao, Jiajun Cui, Jing Yan, Ying Jiang, Qiong Luo, Lujiao Chen, Hetong Li, Yixiao Chen, Zhonghua Shi, Runrun Hao, Xueqi Bai, Zhuoxian Meng, Ting Yu, Zheng Sun, Jianzhong Sheng, Hefeng Huang, Jin Li, Guolian Ding","doi":"10.1126/scitranslmed.adx8909","DOIUrl":"https://doi.org/10.1126/scitranslmed.adx8909","url":null,"abstract":"Gestational diabetes mellitus (GDM) can increase the risk for diabetes in offspring, but the mechanisms underlying the effects of intrauterine hyperglycemia (IHG) on the fetus remain unknown. Here, we show that IHG down-regulated DNA demethylases TET2/3 in fetal pancreatic islets, increased DNA methylation of γ-aminobutyric acid (GABA) synthesis gene <jats:italic toggle=\"yes\">Gad1</jats:italic> , suppressed <jats:italic toggle=\"yes\">Gad1</jats:italic> expression, and elevated somatostatin (SST) protein in the pancreas in mice. Pancreas-specific double knockout (DKO) of <jats:italic toggle=\"yes\">Tet2/3</jats:italic> recapitulates the IHG effects, causing <jats:italic toggle=\"yes\">Gad1</jats:italic> hypermethylation and expression down-regulation, alongside impaired insulin secretion and glucose tolerance. Metabolomic analysis revealed that IHG and <jats:italic toggle=\"yes\">Tet2/3</jats:italic> DKO reduced pancreatic GABA content. Gestational dietary GABA supplementation improved metabolic defects in both IHG and <jats:italic toggle=\"yes\">Tet2/3</jats:italic> DKO models. scRNA-seq analysis of pancreatic islets showed that IHG or <jats:italic toggle=\"yes\">Tet2/3</jats:italic> DKO down-regulated the β cell signature, whereas up-regulating δ cell–related genes, particularly <jats:italic toggle=\"yes\">Sst</jats:italic> , led to the emergence of an <jats:italic toggle=\"yes\">Ins2/Sst</jats:italic> double-positive cell population. β cell–specific deletion of <jats:italic toggle=\"yes\">Sst</jats:italic> rescued IHG-induced metabolic defects. In humans, GDM was associated with reduced GABA content in the umbilical arterial blood. These results uncover an epigenetically controlled pancreatic GABA-SST signaling pathway that may contribute to the GDM-induced increase in offspring diabetes risk and identify dietary GABA supplementation as a potential interventional strategy.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"42 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147351029","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}
Pub Date : 2026-03-04DOI: 10.1126/scitranslmed.adq4529
Harini P. Tirumala, Li Wang, Yan Li, Sameer S. Bajikar, Ashley G. Anderson, Wei Wang, Alexander J. Trostle, Mahla Zahabiyon, Aleksandar Bajic, Jean J. Kim, Hu Chen, Zhandong Liu, Huda Y. Zoghbi
Rett syndrome (RTT) is a neurological disorder caused by loss-of-function mutations in methyl-CpG–binding protein 2 ( MECP2 ), which encodes a transcriptional regulator essential for maintenance of normal neuronal function. The current US Food and Drug Administration–approved treatment for RTT, trofinetide, mildly alleviates some symptoms. In contrast, reintroducing MeCP2 or increasing its amount through transgenesis in mouse RTT models improves most neurological phenotypes and enhances survival. Here, we devised a therapeutic strategy to moderately increase MeCP2 protein by modulating the alternative splicing of MECP2 to switch the less efficiently translated e2 to the more efficiently translated e1 isoform. We deleted Mecp2 exon 2 (unique to e2 ), leading to production of only e1 mRNA, and showed that this up-regulated MeCP2 by 50 to 60% in mice. Next, we investigated the consequences of isoform switching in two independent RTT induced pluripotent stem cell (iPSC)–derived neuron models harboring mutations that reduce both MeCP2 expression and function. Exon 2 deletion in neurons derived from patients with MeCP2-G118E up-regulated MeCP2, ameliorated morphological and electrophysiological changes, and corrected the dysregulated transcriptome in these neurons. Isoform switching in neurons derived from patients with MeCP2-G118E, modeling a severe RTT mutation, only modestly affected MeCP2 protein abundance and, despite this, led to a partial transcriptomic rescue. Last, an exon 2–skipping morpholino up-regulated MeCP2-E1 in vivo in mice. These data set the stage for a potential therapeutic strategy using antisense oligonucleotides to promote isoform switching in patients with RTT who carry partially functioning alleles of MECP2 .
{"title":"Modulating alternative splicing of MECP2 is a potential therapeutic strategy for Rett syndrome","authors":"Harini P. Tirumala, Li Wang, Yan Li, Sameer S. Bajikar, Ashley G. Anderson, Wei Wang, Alexander J. Trostle, Mahla Zahabiyon, Aleksandar Bajic, Jean J. Kim, Hu Chen, Zhandong Liu, Huda Y. Zoghbi","doi":"10.1126/scitranslmed.adq4529","DOIUrl":"https://doi.org/10.1126/scitranslmed.adq4529","url":null,"abstract":"Rett syndrome (RTT) is a neurological disorder caused by loss-of-function mutations in methyl-CpG–binding protein 2 ( <jats:italic toggle=\"yes\">MECP2</jats:italic> ), which encodes a transcriptional regulator essential for maintenance of normal neuronal function. The current US Food and Drug Administration–approved treatment for RTT, trofinetide, mildly alleviates some symptoms. In contrast, reintroducing MeCP2 or increasing its amount through transgenesis in mouse RTT models improves most neurological phenotypes and enhances survival. Here, we devised a therapeutic strategy to moderately increase MeCP2 protein by modulating the alternative splicing of <jats:italic toggle=\"yes\">MECP2</jats:italic> to switch the less efficiently translated <jats:italic toggle=\"yes\">e2</jats:italic> to the more efficiently translated <jats:italic toggle=\"yes\">e1</jats:italic> isoform. We deleted <jats:italic toggle=\"yes\">Mecp2</jats:italic> exon 2 (unique to <jats:italic toggle=\"yes\">e2</jats:italic> ), leading to production of only <jats:italic toggle=\"yes\">e1</jats:italic> mRNA, and showed that this up-regulated MeCP2 by 50 to 60% in mice. Next, we investigated the consequences of isoform switching in two independent RTT induced pluripotent stem cell (iPSC)–derived neuron models harboring mutations that reduce both MeCP2 expression and function. Exon 2 deletion in neurons derived from patients with MeCP2-G118E up-regulated MeCP2, ameliorated morphological and electrophysiological changes, and corrected the dysregulated transcriptome in these neurons. Isoform switching in neurons derived from patients with MeCP2-G118E, modeling a severe RTT mutation, only modestly affected MeCP2 protein abundance and, despite this, led to a partial transcriptomic rescue. Last, an exon 2–skipping morpholino up-regulated MeCP2-E1 in vivo in mice. These data set the stage for a potential therapeutic strategy using antisense oligonucleotides to promote isoform switching in patients with RTT who carry partially functioning alleles of <jats:italic toggle=\"yes\">MECP2</jats:italic> .","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"403 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350625","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}
Pub Date : 2026-03-04DOI: 10.1126/scitranslmed.aea3115
Gerhard Jungwirth, Junguo Cao, Yimin Pan, Rolf Warta, Catharina Lotsch, Mahmoud Moustafa, Maximilian Knoll, Tao Yu, Viktor Braun, Lena Jassowicz, Philip Dao Trong, Zhenlin Wang, Alexander Younsi, Moritz Scherer, Martin Bendszus, Sandro M. Krieg, Andreas von Deimling, Juergen Debus, Amir Abdollahi, Andreas Unterberg, Felix Sahm, Christel Herold-Mende
Managing aggressive meningiomas remains challenging because of limited treatment options besides surgical tumor removal and radiotherapy. To increase the repertoire of promising therapies for aggressive meningiomas, we established a multistep drug screening workflow, focusing on targetable genes obtained from transcriptome data of highly aggressive grade 3 meningiomas. In vitro screening of 107 targeted drugs identified nine effective inhibitors. To study these drugs in a more natural environment, we established a standardized patient-derived tumor organoid (TO) model preserving accurately the original tissue’s genotype and phenotype. Individual drug responses were assessed in TOs from 60 meningioma cases characterized at the molecular level. In particular, the US Food and Drug Administration–approved epigenetic drug panobinostat demonstrated high antimeningioma efficacy in 70% of TOs, mediated through histone deacetylase 1 and 2 (HDAC1/2) inhibition. In addition, treatment in an orthotopic in vivo model revealed improved survival. In search of the molecular mechanism underlying a potentially intrinsic panobinostat resistance, we identified up-regulation of the HDAC8–transforming growth factor–β (TGFβ)–epithelial-to-mesenchymal transition (EMT) axis in the TO model, whereas subsequent HDAC8 depletion increased the sensitivity to panobinostat. These data highlight the utility of personalized drug screenings on TOs to identify suitable drug targets and inhibitors for more effective treatment of clinically aggressive meningiomas and to help advance our understanding of counteracting resistance mechanisms.
{"title":"Drug screening on tumor organoids exposes therapeutic vulnerabilities of meningiomas to HDAC1/2i panobinostat","authors":"Gerhard Jungwirth, Junguo Cao, Yimin Pan, Rolf Warta, Catharina Lotsch, Mahmoud Moustafa, Maximilian Knoll, Tao Yu, Viktor Braun, Lena Jassowicz, Philip Dao Trong, Zhenlin Wang, Alexander Younsi, Moritz Scherer, Martin Bendszus, Sandro M. Krieg, Andreas von Deimling, Juergen Debus, Amir Abdollahi, Andreas Unterberg, Felix Sahm, Christel Herold-Mende","doi":"10.1126/scitranslmed.aea3115","DOIUrl":"https://doi.org/10.1126/scitranslmed.aea3115","url":null,"abstract":"Managing aggressive meningiomas remains challenging because of limited treatment options besides surgical tumor removal and radiotherapy. To increase the repertoire of promising therapies for aggressive meningiomas, we established a multistep drug screening workflow, focusing on targetable genes obtained from transcriptome data of highly aggressive grade 3 meningiomas. In vitro screening of 107 targeted drugs identified nine effective inhibitors. To study these drugs in a more natural environment, we established a standardized patient-derived tumor organoid (TO) model preserving accurately the original tissue’s genotype and phenotype. Individual drug responses were assessed in TOs from 60 meningioma cases characterized at the molecular level. In particular, the US Food and Drug Administration–approved epigenetic drug panobinostat demonstrated high antimeningioma efficacy in 70% of TOs, mediated through histone deacetylase 1 and 2 (HDAC1/2) inhibition. In addition, treatment in an orthotopic in vivo model revealed improved survival. In search of the molecular mechanism underlying a potentially intrinsic panobinostat resistance, we identified up-regulation of the HDAC8–transforming growth factor–β (TGFβ)–epithelial-to-mesenchymal transition (EMT) axis in the TO model, whereas subsequent HDAC8 depletion increased the sensitivity to panobinostat. These data highlight the utility of personalized drug screenings on TOs to identify suitable drug targets and inhibitors for more effective treatment of clinically aggressive meningiomas and to help advance our understanding of counteracting resistance mechanisms.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"31 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350640","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}
Pub Date : 2026-03-04DOI: 10.1126/scitranslmed.adw2603
Akshaya V. Annapragada, Zachariah H. Foda, Hope Orjuela, Carter Norton, Shashikant Koul, Noushin Niknafs, Sarah Short, Keerti Boyapati, Adrianna Bartolomucci, Dimitrios Mathios, Michael Noë, Chris Cherry, Jacob Carey, Alessandro Leal, Bryan Chesnick, Nicholas C. Dracopoli, Jamie E. Medina, Nicholas A. Vulpescu, Daniel C. Bruhm, Sarah Bacus, Vilmos Adleff, Amy K. Kim, Stephen B. Baylin, Gregory D. Kirk, Andrei Sorop, Razvan Iacob, Speranta Iacob, Liana Gheorghe, Simona Dima, Manuel Ramírez-Zea, Katherine A. McGlynn, Claus L. Feltoft, Julia S. Johansen, John Groopman, Jillian Phallen, Robert B. Scharpf, Victor E. Velculescu
Accessible liquid biopsies, including analyses of genome-wide cell-free DNA (cfDNA) fragmentation, are emerging for early detection of cancer but remain largely unexplored in other diseases. Here, we used whole-genome sequencing to examine cfDNA fragmentomes in 1576 individuals, including those with liver disease or with other morbidities such as vascular, autoimmune, and neurodegenerative conditions. As a prototype for disease-specific cfDNA fragmentomic biomarkers, we developed a machine learning classifier that detected early liver disease, advanced fibrosis, and cirrhosis with high sensitivity in separate discovery ( n = 423) and validation cohorts ( n = 221) and had limited cross-reactivity for other diseases. Genome-wide fragmentome and methylome analyses revealed liver-derived and immune-mediated changes in cfDNA in the circulation of individuals affected with liver disease. Fragmentomic changes were also observed across a range of other human morbidities and reflected disease-specific changes in the circulation. A machine learning model using cfDNA fragmentomes predicted overall survival in separate morbidity discovery ( n = 571) and validation cohorts ( n = 231). These analyses demonstrate the connection between cfDNA fragmentomes and an individual’s physiologic state and provide previously unrecognized possibilities for cfDNA liquid biopsies across human disease.
{"title":"Cell-free DNA fragmentomes for noninvasive detection of liver cirrhosis and other diseases","authors":"Akshaya V. Annapragada, Zachariah H. Foda, Hope Orjuela, Carter Norton, Shashikant Koul, Noushin Niknafs, Sarah Short, Keerti Boyapati, Adrianna Bartolomucci, Dimitrios Mathios, Michael Noë, Chris Cherry, Jacob Carey, Alessandro Leal, Bryan Chesnick, Nicholas C. Dracopoli, Jamie E. Medina, Nicholas A. Vulpescu, Daniel C. Bruhm, Sarah Bacus, Vilmos Adleff, Amy K. Kim, Stephen B. Baylin, Gregory D. Kirk, Andrei Sorop, Razvan Iacob, Speranta Iacob, Liana Gheorghe, Simona Dima, Manuel Ramírez-Zea, Katherine A. McGlynn, Claus L. Feltoft, Julia S. Johansen, John Groopman, Jillian Phallen, Robert B. Scharpf, Victor E. Velculescu","doi":"10.1126/scitranslmed.adw2603","DOIUrl":"https://doi.org/10.1126/scitranslmed.adw2603","url":null,"abstract":"Accessible liquid biopsies, including analyses of genome-wide cell-free DNA (cfDNA) fragmentation, are emerging for early detection of cancer but remain largely unexplored in other diseases. Here, we used whole-genome sequencing to examine cfDNA fragmentomes in 1576 individuals, including those with liver disease or with other morbidities such as vascular, autoimmune, and neurodegenerative conditions. As a prototype for disease-specific cfDNA fragmentomic biomarkers, we developed a machine learning classifier that detected early liver disease, advanced fibrosis, and cirrhosis with high sensitivity in separate discovery ( <jats:italic toggle=\"yes\">n</jats:italic> = 423) and validation cohorts ( <jats:italic toggle=\"yes\">n</jats:italic> = 221) and had limited cross-reactivity for other diseases. Genome-wide fragmentome and methylome analyses revealed liver-derived and immune-mediated changes in cfDNA in the circulation of individuals affected with liver disease. Fragmentomic changes were also observed across a range of other human morbidities and reflected disease-specific changes in the circulation. A machine learning model using cfDNA fragmentomes predicted overall survival in separate morbidity discovery ( <jats:italic toggle=\"yes\">n</jats:italic> = 571) and validation cohorts ( <jats:italic toggle=\"yes\">n</jats:italic> = 231). These analyses demonstrate the connection between cfDNA fragmentomes and an individual’s physiologic state and provide previously unrecognized possibilities for cfDNA liquid biopsies across human disease.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350637","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}
Pub Date : 2026-02-25DOI: 10.1126/scitranslmed.aea7097
Asa Thibodeau, Asuncion Mejias, Djamel Nehar-Belaid, Radu Marches, Zhaohui Xu, Giray Eryilmaz, Steven Z. Josefowicz, Bart Jones, Marie Wehenkel, Silke Paust, Virginia Pascual, Jacques Banchereau, Octavio Ramilo, Duygu Ucar
Respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in infants differ substantially in their clinical presentations and outcomes. RSV is the leading cause of severe lower respiratory tract infection in infants, whereas SARS-CoV-2 infections are typically milder and do not necessarily involve the lower respiratory tract. To uncover immune mechanisms associated with these differences, we analyzed blood samples from infants (median age, 2.3 months) infected with RSV ( n = 19) or SARS-CoV-2 ( n = 30), as well as healthy control infants ( n = 17), using cytokine profiling, single-cell transcriptomics, and epigenomics. Both viruses induced comparable interferon-stimulated gene signatures but displayed disease-specific signatures in the individual cell types analyzed. Specifically, RSV was associated with increased CD4 + terminal effector memory T cell and memory regulatory T cell frequencies in the peripheral blood. Infants with severe RSV had reduced natural killer cell frequencies in the blood, lower IFNG expression in CD56 dim natural killer cells, and diminished chromatin accessibility at T-BET and EOMES binding sites in CD56 dim and CD56 bright natural killer cells. In contrast, infants infected with SARS-CoV-2 showed heightened proinflammatory responses in the blood, including higher nuclear factor κB pathway activity and serum tumor necrosis factor concentrations. These results highlight the distinct nature of infant immune responses to RSV and SARS-CoV-2 infections, offering insights that may help explain differences in the clinic and guide therapies.
{"title":"A systems immunology approach reveals divergent immune profiles of RSV and SARS-CoV-2 infections in infants","authors":"Asa Thibodeau, Asuncion Mejias, Djamel Nehar-Belaid, Radu Marches, Zhaohui Xu, Giray Eryilmaz, Steven Z. Josefowicz, Bart Jones, Marie Wehenkel, Silke Paust, Virginia Pascual, Jacques Banchereau, Octavio Ramilo, Duygu Ucar","doi":"10.1126/scitranslmed.aea7097","DOIUrl":"https://doi.org/10.1126/scitranslmed.aea7097","url":null,"abstract":"Respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in infants differ substantially in their clinical presentations and outcomes. RSV is the leading cause of severe lower respiratory tract infection in infants, whereas SARS-CoV-2 infections are typically milder and do not necessarily involve the lower respiratory tract. To uncover immune mechanisms associated with these differences, we analyzed blood samples from infants (median age, 2.3 months) infected with RSV ( <jats:italic toggle=\"yes\">n</jats:italic> = 19) or SARS-CoV-2 ( <jats:italic toggle=\"yes\">n</jats:italic> = 30), as well as healthy control infants ( <jats:italic toggle=\"yes\">n</jats:italic> = 17), using cytokine profiling, single-cell transcriptomics, and epigenomics. Both viruses induced comparable interferon-stimulated gene signatures but displayed disease-specific signatures in the individual cell types analyzed. Specifically, RSV was associated with increased CD4 <jats:sup>+</jats:sup> terminal effector memory T cell and memory regulatory T cell frequencies in the peripheral blood. Infants with severe RSV had reduced natural killer cell frequencies in the blood, lower <jats:italic toggle=\"yes\">IFNG</jats:italic> expression in CD56 <jats:sup>dim</jats:sup> natural killer cells, and diminished chromatin accessibility at T-BET and EOMES binding sites in CD56 <jats:sup>dim</jats:sup> and CD56 <jats:sup>bright</jats:sup> natural killer cells. In contrast, infants infected with SARS-CoV-2 showed heightened proinflammatory responses in the blood, including higher nuclear factor κB pathway activity and serum tumor necrosis factor concentrations. These results highlight the distinct nature of infant immune responses to RSV and SARS-CoV-2 infections, offering insights that may help explain differences in the clinic and guide therapies.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"342 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147278782","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}
Pub Date : 2026-02-25DOI: 10.1126/scitranslmed.ady2936
Alexander Arnuk, Cuijuan Han, Abimbola E. Lawal, Bofei Wang, Sadik Karma, Zhiping Zhang, Mhd Yousuf Yassouf, Sakthi Harini Rajendran, Harshpreet Chandok, Madeline L. Eller, Sogand Sajedi, Meryl McKenna, Eve Herman, Louisa Hagen, Bettina Nadorp, Zengshuo Mo, Hector Orellana, Aristotelis Tsirigos, Pedro Miura, Hussein A. Abbas, Iannis Aifantis, Eric Wang
Inactivation of tumor suppressor genes (TSGs) imparts a cellular fitness in cancers, including in acute myeloid leukemia (AML). The detection of silenced TSGs without direct mutations presents challenges in designing targeted cancer treatments, yet it also opens a therapeutic opportunity to restore their function. In this study, we identified the transcriptional repressor ZBTB7A as a TSG that is down-regulated in samples from patients with AML and is associated with poor survival outcomes. Loss of ZBTB7A amplifies TNF signaling, driving a dysfunctional inflammatory state that accelerates AML progression in vivo. Mechanistically, the mRNA decay factor ZFP36L2 binds to the 3′ untranslated region (3′UTR) of ZBTB7A , promoting its transcript degradation in human AML cells. To identify therapeutic targets, we developed a CRISPR-based screening approach coupled with fluorescence in situ hybridization and flow cytometry (FISH-Flow), pinpointing the KDM4 family of histone demethylases as a vulnerability to restore ZBTB7A function. Pharmacologic inhibition of KDM4 up-regulated ZBTB7A expression, promoted terminal differentiation in patient-derived xenograft models, and demonstrated broad antileukemic efficacy across AML subtypes as well as preserved normal hematopoiesis. These findings reveal regulatory mechanisms of ZBTB7A and support epigenetic therapy as a promising strategy to reactivate its tumor suppressor function in hematologic cancers.
{"title":"Epigenetic reactivation of the tumor suppressor ZBTB7A by KDM4 inhibition in human acute myeloid leukemia","authors":"Alexander Arnuk, Cuijuan Han, Abimbola E. Lawal, Bofei Wang, Sadik Karma, Zhiping Zhang, Mhd Yousuf Yassouf, Sakthi Harini Rajendran, Harshpreet Chandok, Madeline L. Eller, Sogand Sajedi, Meryl McKenna, Eve Herman, Louisa Hagen, Bettina Nadorp, Zengshuo Mo, Hector Orellana, Aristotelis Tsirigos, Pedro Miura, Hussein A. Abbas, Iannis Aifantis, Eric Wang","doi":"10.1126/scitranslmed.ady2936","DOIUrl":"https://doi.org/10.1126/scitranslmed.ady2936","url":null,"abstract":"Inactivation of tumor suppressor genes (TSGs) imparts a cellular fitness in cancers, including in acute myeloid leukemia (AML). The detection of silenced TSGs without direct mutations presents challenges in designing targeted cancer treatments, yet it also opens a therapeutic opportunity to restore their function. In this study, we identified the transcriptional repressor <jats:italic toggle=\"yes\">ZBTB7A</jats:italic> as a TSG that is down-regulated in samples from patients with AML and is associated with poor survival outcomes. Loss of ZBTB7A amplifies TNF signaling, driving a dysfunctional inflammatory state that accelerates AML progression in vivo. Mechanistically, the mRNA decay factor ZFP36L2 binds to the 3′ untranslated region (3′UTR) of <jats:italic toggle=\"yes\">ZBTB7A</jats:italic> , promoting its transcript degradation in human AML cells. To identify therapeutic targets, we developed a CRISPR-based screening approach coupled with fluorescence in situ hybridization and flow cytometry (FISH-Flow), pinpointing the KDM4 family of histone demethylases as a vulnerability to restore ZBTB7A function. Pharmacologic inhibition of KDM4 up-regulated ZBTB7A expression, promoted terminal differentiation in patient-derived xenograft models, and demonstrated broad antileukemic efficacy across AML subtypes as well as preserved normal hematopoiesis. These findings reveal regulatory mechanisms of ZBTB7A and support epigenetic therapy as a promising strategy to reactivate its tumor suppressor function in hematologic cancers.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"51 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147278803","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}
Adult mammalian central nervous system (CNS) axons do not spontaneously regenerate after injury. We recently identified multiple genes that promote optic nerve regeneration, protect retinal ganglion cell (RGC) somata and axons, and preserve visual function in mouse glaucoma models. Here, we investigated the downstream molecular mechanisms driving the regenerative and neuroprotective effects of the actin depolymerization molecule gelsolin ( Gsn , one of the top up-regulated genes in regenerating RGCs) and the actin regulatory molecules (annexin A2, destrin, cofilin, profilin, latrunculin, and cytochalasin). Adeno-associated virus (AAV)–mediated specific expression of these genes in RGCs or topical delivery of small molecules promoted optic nerve regeneration and RGC protection in an optic nerve crush model and an ocular hypertension glaucoma mouse model. These regenerative effects were associated with a decrease in F-actin in axon shafts. Ex vivo mechanistic studies, furthermore, demonstrated that actin depolymerization enhances axonal mitochondrial transport in RGC axons, suggesting a mechanistic nodal point on which these pro-regeneration molecules converge. We showed that the natural compound latrunculin B targets this unified mechanism in both mouse and human RGCs to promote axon outgrowth. In addition, we detected up-regulated F-actin in aqueous humors of patients with severe glaucoma, emphasizing the translational potential of our findings.
{"title":"Actin depolymerization promotes axon regeneration by restoring axonal mitochondrial transport in mouse models of optic neuropathy","authors":"Liang Li, Xue Feng, Fang Fang, Jinyu Fei, Jenny Lu, Huiying Zhang, Michaela Dujava Ždímalová, Yuan Yuan, Ziming Luo, Haoliang Huang, Dong Liu, Fengwen Huang, Hao Liu, Yuyang Zeng, Fuyun Bian, Mingshen Ma, In-Jee You, Liang Liu, Xiaoqin Yan, Mu Li, Yan Lin, Qinghong Xie, Arjun Krish, Xin Duan, Jeffrey Louis Goldberg, Xiaoke Chen, Marcus Braun, Zdenek Lansky, Ying Han, Ruobo Zhou, Yang Hu","doi":"10.1126/scitranslmed.adw0908","DOIUrl":"https://doi.org/10.1126/scitranslmed.adw0908","url":null,"abstract":"Adult mammalian central nervous system (CNS) axons do not spontaneously regenerate after injury. We recently identified multiple genes that promote optic nerve regeneration, protect retinal ganglion cell (RGC) somata and axons, and preserve visual function in mouse glaucoma models. Here, we investigated the downstream molecular mechanisms driving the regenerative and neuroprotective effects of the actin depolymerization molecule gelsolin ( <jats:italic toggle=\"yes\">Gsn</jats:italic> , one of the top up-regulated genes in regenerating RGCs) and the actin regulatory molecules (annexin A2, destrin, cofilin, profilin, latrunculin, and cytochalasin). Adeno-associated virus (AAV)–mediated specific expression of these genes in RGCs or topical delivery of small molecules promoted optic nerve regeneration and RGC protection in an optic nerve crush model and an ocular hypertension glaucoma mouse model. These regenerative effects were associated with a decrease in F-actin in axon shafts. Ex vivo mechanistic studies, furthermore, demonstrated that actin depolymerization enhances axonal mitochondrial transport in RGC axons, suggesting a mechanistic nodal point on which these pro-regeneration molecules converge. We showed that the natural compound latrunculin B targets this unified mechanism in both mouse and human RGCs to promote axon outgrowth. In addition, we detected up-regulated F-actin in aqueous humors of patients with severe glaucoma, emphasizing the translational potential of our findings.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"342 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147278805","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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