Science Translational Medicine最新文献

{"title":"Myeloid MAS–driven macrophage efferocytosis promotes resolution in ischemia-stressed mouse and human livers","authors":"Shuai Chen,&nbsp;Bingyuan Huang,&nbsp;Shanshan Li,&nbsp;Zhijing Wang,&nbsp;Yizhong Chang,&nbsp;Huaming Huang,&nbsp;Chun Liu,&nbsp;Shuo Zhang,&nbsp;Manchang Jin,&nbsp;Haoyu Jia,&nbsp;Bo Yang,&nbsp;Ziwen Tao,&nbsp;Li Chen,&nbsp;Kai Guo,&nbsp;Zhi Lu,&nbsp;Jing Li,&nbsp;Fei Wang,&nbsp;Changqing Yang","doi":"10.1126/scitranslmed.adr2725","DOIUrl":"10.1126/scitranslmed.adr2725","url":null,"abstract":"<div >Liver ischemia-reperfusion injury (LIRI) is an inevitable detrimental event after liver transplantation. The MAS receptor plays a protective role in various diseases. However, the specific roles of MAS in myeloid cell innate immunity and the maintenance of hepatic tissue homeostasis remain unclear. Here, we showed that mice with systemic, Kupffer cell–specific, or myeloid cell–specific <i>Mas1</i> deficiency were vulnerable to LIRI. Single-cell RNA sequencing, spatial transcriptomics, and intravital imaging revealed that myeloid deficiency of <i>Mas1</i> resulted in impaired macrophage efferocytosis by down-regulating MER tyrosine kinase (MERTK), leading to the accumulation of aged neutrophils and exacerbation of inflammation and pathology. Mechanistic studies indicated that the MAS receptor regulated the Krüppel-like factor 4 (KLF4)/MERTK axis in macrophages via the protein kinase A (PKA)/cAMP response element–binding protein (CREB) signaling pathway. KLF4 directly bound to the promoter region of MERTK and transcriptionally promoted its expression in macrophages, leading to attenuation of the liver inflammatory response. Macrophage-specific knockout of KLF4 and MERTK in the mice also resulted in impaired macrophage efferocytosis with the accumulation of aged neutrophils. Macrophage-specific overexpression of KLF4 in vivo effectively reversed the phenotype exacerbated by myeloid <i>Mas1</i> deficiency. In addition, we demonstrated that MAS⁺MERTK⁺ macrophages actively migrated toward aged neutrophils in ischemia-stressed human livers, thereby promptly clearing aged neutrophils. In summary, this study documented the regulatory function of the MAS/KLF4/MERTK axis in macrophage efferocytosis via PKA/CREB signaling. This axis may thus serve as a therapeutic target and checkpoint regulator of homeostasis in response to LIRI.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 806","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586889","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":"Adenovirus and mRNA vaccines as well as mucosal boosting improve protective efficacy against influenza virus challenge in macaques","authors":"Catherine Jacob-Dolan,&nbsp;David Hope,&nbsp;Jinyan Liu,&nbsp;Alejandra Waller-Pulido,&nbsp;Brookelynne Verrette,&nbsp;Dalia N. Cabrera-Barragan,&nbsp;Samuel J. Nangle,&nbsp;Qixin Wang,&nbsp;Ross Blanc,&nbsp;Jana Fisher,&nbsp;Ninaad Lasrado,&nbsp;Liping Wang,&nbsp;Anthony Cook,&nbsp;Laurent Pessiant,&nbsp;Mark Lewis,&nbsp;Hanne Andersen,&nbsp;Markay Hopps,&nbsp;Ingrid L. Scully,&nbsp;Pirada Suphaphiphat Allen,&nbsp;Ryan P. McNamara,&nbsp;Annaliesa S. Anderson,&nbsp;Dan H. Barouch","doi":"10.1126/scitranslmed.adu7646","DOIUrl":"10.1126/scitranslmed.adu7646","url":null,"abstract":"<div >The clinically approved seasonal influenza vaccines provide only 10 to 60% efficacy, necessitating strategies to improve vaccine performance. Here, we explored strategies for improving influenza vaccine efficacy using gene-based vaccines and mucosal boosting strategies in nonhuman primates. All vaccinated cynomolgus macaques were primed with the clinical quadrivalent inactivated virus (QIV) vaccine. We evaluated a rhesus adenovirus (RhAd52) vector delivered by intramuscular or mucosal routes and an mRNA vaccine encoding the hemagglutinin of A/H1N1/Wisconsin/67/2022 delivered intramuscularly as boosts compared with the QIV vaccine delivered intramuscularly and the quadrivalent live-attenuated influenza virus (LAIV) vaccine delivered intranasally. Boosting with RhAd52 and mRNA vaccines induced more robust humoral and cellular immune responses than the clinically approved vaccines and provided improved protective efficacy against a high-dose homologous challenge with A/H1N1/Wisconsin/67/2022. The RhAd52 vaccine delivered by the intratracheal route elicited robust mucosal antibody and T cell responses and provided optimal protection in the upper and lower respiratory tracts. Both peripheral and mucosal antibody responses, as well as mucosal T cell responses, correlated with protection against viral loads. Altogether, this study defines strategies for improving H1N1 seasonal influenza vaccine efficacy by using gene-based vaccines and by optimizing mucosal immunity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 806","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adu7646","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586887","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":"Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease","authors":"Lindsay B. Tulloch,&nbsp;Hugh Tawell,&nbsp;Annie E. Taylor,&nbsp;Marta Lopes Lima,&nbsp;Alice Dawson,&nbsp;Sandra Carvalho,&nbsp;Richard J. Wall,&nbsp;Victoriano Corpas-Lopez,&nbsp;Gourav Dey,&nbsp;Jack Duggan,&nbsp;Luma Godoy Magalhaes,&nbsp;Leah S. Torrie,&nbsp;Laura Frame,&nbsp;David Robinson,&nbsp;Stephen Patterson,&nbsp;Michele Tinti,&nbsp;George W. Weaver,&nbsp;William J. Robinson,&nbsp;Monica Cal,&nbsp;Marcel Kaiser,&nbsp;Pascal Mäser,&nbsp;Peter Sjö,&nbsp;Benjamin Perry,&nbsp;John M. Kelly,&nbsp;Amanda Fortes Francisco,&nbsp;Avninder S. Bhambra,&nbsp;Susan Wyllie","doi":"10.1126/scitranslmed.adu4564","DOIUrl":"10.1126/scitranslmed.adu4564","url":null,"abstract":"<div >The protozoan parasite <i>Trypanosoma cruzi</i> causes Chagas disease, which is among the deadliest parasitic infections in Latin America. Current therapies are toxic and lack efficacy against the chronic stage of infection; thus, new drugs are urgently needed. Here, we describe a previously unidentified series of quinazoline compounds with potential against <i>Trypanosoma cruzi</i> and the related trypanosomatid parasites <i>Trypanosoma brucei</i> and <i>Leishmania donovani</i>. We demonstrated partial efficacy of a lead quinazoline compound in a mouse model of acute Chagas disease. Mechanism of action studies using several orthogonal approaches showed that this quinazoline compound series targeted the ATP-binding pocket of <i>T. cruzi</i> lysyl-tRNA synthetase 1 (KRS1). A high-resolution crystal structure of KRS1 bound to the drug indicated binding interactions that led to KRS1 inhibition. Our study identified KRS1 as a druggable target for treating <i>T. cruzi</i> infection in a mouse model. This quinazoline series shows potential for treating Chagas disease but will require further development to become a future treatment for this neglected disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 806","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586838","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":"Myeloma interaction with bone marrow stromal cells suppresses ciliogenesis and osteogenic potential in myeloma bone disease","authors":"Ying Xie,&nbsp;Zhaoyun Liu,&nbsp;Qian Li,&nbsp;Tiantian Li,&nbsp;Jing Guo,&nbsp;Meilin Hu,&nbsp;Jiantao Sun,&nbsp;Hongmei Jiang,&nbsp;Jingya Wang,&nbsp;Sheng Wang,&nbsp;Jingjing Wang,&nbsp;Yixuan Wang,&nbsp;Ziyi Peng,&nbsp;Mengqi Wang,&nbsp;Xin Li,&nbsp;Yangyang Xie,&nbsp;Hao Cheng,&nbsp;Linchuang Jia,&nbsp;Danchen Su,&nbsp;Mu Qiao,&nbsp;Jia Song,&nbsp;Xiaozhi Liu,&nbsp;Rong Fu,&nbsp;Zhiqiang Liu","doi":"10.1126/scitranslmed.adq2961","DOIUrl":"10.1126/scitranslmed.adq2961","url":null,"abstract":"<div >Myeloma bone disease, a complication of multiple myeloma (MM), is characterized by impaired osteogenic function of bone marrow stromal cells (BMSCs) and can be an indicator of disease progression. The underlying mechanisms driving BMSC dysfunction are not yet fully understood. This work investigated MM cell interaction with BMSCs, finding that BMSC ciliogenesis is inhibited in the presence of myeloma cells. We demonstrated that direct interaction between myeloma cells and BMSCs through CD40-CD40L led to BMSC down-regulation of sentrin-specific protease 1 (SENP1), a cysteine protease that removes small ubiquitin-like modifier (SUMO) posttranslational modifications. SENP1 down-regulation led to increased SUMOylation of oral-facial-digital syndrome type 1 protein (OFD1), a centriole and centriolar satellite protein, at K931. Increased SUMOylation led to increased OFD1 protein stability and localization at centriolar satellites of primary cilia and decreased ciliogenesis. Consequently, BMSCs lacking primary cilia became desensitized to shear stress stimulation and decreased Hedgehog signaling activation. This cascade of events resulted in inhibited ciliogenesis and osteogenesis in myeloma-BMSC–interacting models, in <i>Prx1</i>^Cre<i>Cd40l</i>^f/f mice, and in clinical samples. Treatment with an anti-CD40 neutralizing antibody effectively mitigated bone disruption and tumor burden in the Vk*MYC and SCID (severe combined immunodeficient)–hu mouse models of MM. Overall, our study provides experimental insights into BMSC dysfunction in MM and suggests that targeting the CD40-SENP1-OFD1 axis could hold promise for MM treatment in clinical settings.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 806","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587053","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":"Regulatory T cells attenuate chronic inflammation and cardiac fibrosis in hypertrophic cardiomyopathy","authors":"Ying-Jie Wang,&nbsp;Kamayani Singh,&nbsp;Adam B. Lokman,&nbsp;Siwei Deng,&nbsp;Balaraju Sunitha,&nbsp;Jose Coelho Lima Jr.,&nbsp;Julia Beglov,&nbsp;Matthew Kelly,&nbsp;Andrew Blease,&nbsp;Jacky C. K. Fung,&nbsp;Anan Huang,&nbsp;Moustafa Attar,&nbsp;Lee-Anne Stork,&nbsp;Mahon L. Maguire,&nbsp;Jürgen E. Schneider,&nbsp;Steve B. Marston,&nbsp;Elizabeth J. Soilleux,&nbsp;Calliope A. Dendrou,&nbsp;Mark Coles,&nbsp;Christopher D. Buckley,&nbsp;Jonathan G. Seidman,&nbsp;Christine E. Seidman,&nbsp;Charles Redwood,&nbsp;Houman Ashrafian,&nbsp;Hugh Watkins","doi":"10.1126/scitranslmed.adq3516","DOIUrl":"10.1126/scitranslmed.adq3516","url":null,"abstract":"<div >Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart muscle disorder. Although the biophysical mechanisms by which gene variants in sarcomeric proteins disrupt cardiomyocyte function are largely understood, the cellular and molecular pathways leading to the complex, variable, and adverse remodeling of the non-myocyte compartment are unexplained. Here, we report that postmortem and explanted human HCM hearts exhibited chronic focal leukocyte infiltration and prominent activation of immune cells. Gene set enrichment analysis (GSEA) revealed that active immune responses were present in the mid- and late-stage HCM human hearts and in mouse hearts from several HCM mouse models. The alpha cardiac actin 1-E99K (<i>Actc1</i>^E99K) HCM mouse model was selected for the study because it closely recapitulates the features of progressive remodeling and fibrosis seen in advanced disease in patients. Genetic depletion of lymphocytes in recombination activating gene 1–knockout (<i>Rag-1</i>^KO) mice led to marked exacerbation of adverse cardiac remodeling in the <i>Actc1</i>^E99K mice. Detailed characterization of cardiac regulatory T cells (T_reg cells) demonstrated a time-dependent increase in <i>Actc1</i>^E99K hearts with altered immunosuppressive profiles. Adoptive transfer of splenic T_reg cells reduced cardiac fibrosis and improved systolic dysfunction in <i>Actc1</i>^E99K mice with or without lymphocytes. In addition, low-dose interleukin-2 (IL-2)/anti–IL-2 complex (IL-2/c), which specifically induced T_reg cell expansion in vivo, ameliorated cardiac fibrosis and reduced macrophage infiltration and activation in <i>Actc1</i>^E99K mice. These data contribute to our understanding of HCM and support the use of T_reg cells as a clinically testable therapeutic strategy for cardiac fibrosis in the HCM heart.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 806","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586888","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":"Neuronal HDAC3 knockdown promotes propriospinal detour pathway formation and locomotor recovery in a mouse model of spinal cord injury","authors":"Zhongyang Gao,&nbsp;Hongyuan Xing,&nbsp;Yifan Shen,&nbsp;Xin Ding,&nbsp;Shibo Xu,&nbsp;Run Li,&nbsp;Yijian Zhang,&nbsp;Susu Mao,&nbsp;Can Liu,&nbsp;Jiale Jin,&nbsp;Yang Liu,&nbsp;Siyuan Wang,&nbsp;Chunyang Xing,&nbsp;Zhiyun Feng,&nbsp;Xigong Li,&nbsp;Mengran Jin,&nbsp;Yuhai Wang,&nbsp;Xijing He,&nbsp;Xuelian He,&nbsp;Yan Liu,&nbsp;Xuesong Zhu,&nbsp;Yuanyuan Liu,&nbsp;Yang Yang,&nbsp;Yue Wang","doi":"10.1126/scitranslmed.adp1873","DOIUrl":"10.1126/scitranslmed.adp1873","url":null,"abstract":"<div >Propriospinal detour pathways facilitate motor recovery after spinal cord injury (SCI). Here, through a screen of epigenetic modulators, we demonstrated that small interfering RNA (siRNA)–mediated knockdown of histone deacetylase 3, delivered by extracellular vesicles (EVsiHDAC3), promoted neurite outgrowth in murine spinal neurons and human induced pluripotent stem cell–derived sensory and motor neurons. To enhance in vivo efficacy, we developed a neurotrophic nanoparticle platform using gelatin methacryloyl microspheres conjugated with an optimized rabies glycoprotein–derived peptide. Spinal delivery of the EVsiHDAC3-loaded platform (oGHDAC3) or adeno-associated virus–mediated neuronal HDAC3 deletion facilitated propriospino-lumbar detour circuit formation and improved locomotion after staggered double hemisection SCI in mice. Chemogenetic silencing of propriospinal relay neurons compromised recovered stepping upon oGHDAC3 treatment. We observed no therapeutic effects of oGHDAC3 after full spinal transection in mice, further suggesting that spared intraspinal circuits serve as the neural substrates for locomotion recovery. Mechanistically, Stat3 deletion in interlesional neurons, combined with mTOR inactivation, abolished the beneficial effects of oGHDAC3. Finally, combining oGHDAC3 with CLP290, a KCC2 agonist, further improved detour circuit functionality, resulting in consistent weight-supported stepping. Our findings suggest that integrating siRNA-mediated HDAC3 inhibition with a neurotropic bionanomaterial platform could be a translatable approach for restoring motor function after incomplete SCI.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 806","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586840","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":"Modeling lesion transition dynamics to clinically characterize patients with clade I mpox in the Democratic Republic of the Congo","authors":"Takara Nishiyama,&nbsp;Fuminari Miura,&nbsp;Yong Dam Jeong,&nbsp;Naotoshi Nakamura,&nbsp;Hyeongki Park,&nbsp;Masahiro Ishikane,&nbsp;Shotaro Yamamoto,&nbsp;Noriko Iwamoto,&nbsp;Michiyo Suzuki,&nbsp;Ayana Sakurai,&nbsp;Kazuyuki Aihara,&nbsp;Koichi Watashi,&nbsp;William S. Hart,&nbsp;Robin N. Thompson,&nbsp;Yasuhiro Yasutomi,&nbsp;Norio Ohmagari,&nbsp;Placide Mbala Kingebeni,&nbsp;John W. Huggins,&nbsp;Shingo Iwami,&nbsp;Phillip R. Pittman","doi":"10.1126/scitranslmed.ads4773","DOIUrl":"10.1126/scitranslmed.ads4773","url":null,"abstract":"<div >Coinciding with the global outbreak of clade IIb mpox virus (MPXV), the Democratic Republic of the Congo (DRC) recently experienced a rapid surge in mpox cases with clade I MPXV. On 14 August 2024, the World Health Organization declared the continued cross-border spread of this clade in Africa a public health emergency of international concern (PHEIC). Clade I MPXV is known to be more fatal than clade IIb, but its clinical characteristics and prognosis differ between patients. Here, we used mathematical modeling to quantify temporal changes in total lesion counts during clade I MPXV infections, using data from a large cohort of patients with mpox in the DRC from 2007 to 2011. We further analyzed individuals’ clinical data to explore predictive biomarkers of high lesion counts. Our analysis indicates that patients with clade I mpox can be stratified into two groups according to lesion severity and that viral load in peripheral blood at symptom onset may serve as a predictor for this classification [area under the curve (AUC) = 0.70]. Our estimates also suggest substantial individual heterogeneity in the time period during which patients have lesions, ranging from 20 to 65 days. Understanding the severity and duration of lesions in different patients, as characterized by our approach, may contribute to more tailored treatment strategies and control measures in ongoing clade I mpox outbreaks.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 805","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.ads4773","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537343","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":"Targeting HBV with RNA interference: Paths to cure","authors":"Matteo Iannacone,&nbsp;Cristian G. Beccaria,&nbsp;Lena Allweiss,&nbsp;Julie Lucifora,&nbsp;John E. Tavis,&nbsp;Adam J. Gehring,&nbsp;Maura Dandri","doi":"10.1126/scitranslmed.adv3678","DOIUrl":"10.1126/scitranslmed.adv3678","url":null,"abstract":"<div >Chronic hepatitis B virus (HBV) infection affects millions worldwide despite the availability of effective vaccines. The stability of HBV’s genomic minichromosome (cccDNA) within hepatocytes, the persistence of integrated viral sequences capable of producing viral antigens, and the ability of the virus to evade immune control all contribute to the difficulty in achieving a functional cure. Existing antiviral treatments have minimal impact on HBV transcription, allowing persistent viral antigen production and immune dysfunction. Emerging RNA interference (RNAi) therapies targeting HBV RNAs reduce viral replication, antigen expression, and, in turn, cccDNA activity, providing a potential path to a functional cure.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 805","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537324","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":"A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain metastasis","authors":"Shawn C. Chafe,&nbsp;Kui Zhai,&nbsp;Nikoo Aghaei,&nbsp;Petar Miletic,&nbsp;Zhi Huang,&nbsp;Kevin R. Brown,&nbsp;Daniel Mobilio,&nbsp;Daniel Young,&nbsp;Yujin Suk,&nbsp;Shan Grewal,&nbsp;Dillon McKenna,&nbsp;Zahra Alizada,&nbsp;Agata M. Kieliszek,&nbsp;Fred C. Lam,&nbsp;Laura Escudero,&nbsp;Qian Huang,&nbsp;Ariana Huebner,&nbsp;Jack Lu,&nbsp;Patrick Ang,&nbsp;Alisha Anand,&nbsp;Stefan Custers,&nbsp;Erika Apel,&nbsp;Sarah Slassi,&nbsp;Benjamin Brakel,&nbsp;Jongmyung Kim,&nbsp;James K. C. Liu,&nbsp;Blessing Iquo Bassey-Archibong,&nbsp;Rober Abdo,&nbsp;Yaron Shargall,&nbsp;Jian-Qiang Lu,&nbsp;Jean-Claude Cutz,&nbsp;Qi Zhang,&nbsp;Shawn Shun-Cheng Li,&nbsp;Chitra Venugopal,&nbsp;Robert E. Hynds,&nbsp;Antoine Dufour,&nbsp;Jason Moffat,&nbsp;Charles Swanton,&nbsp;Shideng Bao,&nbsp;Sheila K. Singh","doi":"10.1126/scitranslmed.adu2459","DOIUrl":"10.1126/scitranslmed.adu2459","url":null,"abstract":"<div >Brain metastasis occurs in up to 40% of patients with non–small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumor and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome-wide CRISPR activation screen to identify molecular drivers of brain metastasis from an orthotopic xenograft model derived from a patient with NSCLC. We found that activating expression of the Alzheimer’s disease–associated beta-secretase 1 (BACE1) led to a substantial increase in brain metastases. Furthermore, genetic and pharmacological inhibition of BACE1 blocked NSCLC brain metastasis. Mechanistically, we identified that BACE1 acts through epidermal growth factor receptor to drive this metastatic phenotype. Together, our data highlight the power of in vivo CRISPR activation screening to unveil molecular drivers and potential therapeutic targets of NSCLC brain metastasis.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 805","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537350","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":"Growth arrest specific–6 and angiotoxin receptor–like signaling drive oral regenerative wound repair","authors":"Michelle F. Griffin,&nbsp;Jessica Cook,&nbsp;Annah Morgan,&nbsp;Dario Boffelli,&nbsp;Mauricio Downer,&nbsp;Amanda F. Spielman,&nbsp;Nicholas J. Guardino,&nbsp;Jason L. Guo,&nbsp;Jennifer B. L. Parker,&nbsp;Michael Januszyk,&nbsp;Caleb Valencia,&nbsp;Maxwell Kuhnert,&nbsp;John Lu,&nbsp;Rachel Zwick,&nbsp;Derrick C. Wan,&nbsp;Ophir D. Klein,&nbsp;Michael T. Longaker","doi":"10.1126/scitranslmed.adk2101","DOIUrl":"10.1126/scitranslmed.adk2101","url":null,"abstract":"<div >Rapid and scarless wound repair is a hallmark of the oral mucosa, yet the cellular and molecular mechanisms that enable this regeneration remain unclear. By comparing populations of murine oral mucosal fibroblasts (OMFs) and facial skin fibroblasts (FSFs), we have identified mechanisms that facilitate regeneration over fibrosis. We found that OMFs used growth arrest specific–6 (GAS6)–angiotoxin receptor–like (AXL) signaling to suppress fibrosis-related mechanosignaling through focal adhesion kinase (FAK) in vitro. Inhibition or knockdown of AXL in the murine oral mucosa resulted in fibrotic wounds and increased activation of FAK. Stimulation of AXL by exogenous GAS6 in the murine facial skin yielded wounds that healed regeneratively as assessed by collagen deposition and organization. Rare human oral scars that resulted from repetitive injury showed decreased expression of GAS6 and AXL and increased FAK. Activating AXL by exogenous GAS6 in repetitively injured mouse oral tissue resulted in better wound healing outcomes and reduced scarring. Altogether, we show that AXL signaling is necessary for murine regenerative wound healing in the oral mucosa and sufficient to limit facial skin fibrosis.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 805","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537354","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}