Science Advances最新文献_第9页

Mycobacterium tuberculosis phagosome Ca2+ leakage triggers multimembrane ATG8/LC3 lipidation to restrict damage in human macrophages

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-03-26 DOI: 10.1126/sciadv.adt3311

Di Chen, Antony Fearns, Maximiliano G. Gutierrez

{"title":"Mycobacterium tuberculosis phagosome Ca2+ leakage triggers multimembrane ATG8/LC3 lipidation to restrict damage in human macrophages","authors":"Di Chen, Antony Fearns, Maximiliano G. Gutierrez","doi":"10.1126/sciadv.adt3311","DOIUrl":"10.1126/sciadv.adt3311","url":null,"abstract":"<div >The role of canonical autophagy in controlling <i>Mycobacterium tuberculosis</i> (Mtb), referred to as xenophagy, is understood to involve targeting Mtb to autophagosomes, which subsequently fuse with lysosomes for degradation. Here, we found that Ca<sup>2+</sup> leakage after Mtb phagosome damage in human macrophages is the signal that triggers autophagy-related protein 8/microtubule-associated proteins 1A/1B light chain 3 (ATG8/LC3) lipidation. Unexpectedly, ATG8/LC3 lipidation did not target Mtb to lysosomes, excluding the canonical xenophagy. Upon Mtb phagosome damage, the Ca<sup>2+</sup> leakage–dependent ATG8/LC3 lipidation occurred on multiple membranes instead of single or double membranes excluding the noncanonical autophagy pathways. Mechanistically, Ca<sup>2+</sup> leakage from the phagosome triggered the recruitment of the V-ATPase–ATG16L1 complex independently of FIP200, ATG13, and proton gradient disruption. Furthermore, the Ca<sup>2+</sup> leakage–dependent ATG8/LC3 lipidation limited Mtb phagosome damage and restricted Mtb replication. Together, we uncovered Ca<sup>2+</sup> leakage as the key signal that triggers ATG8/LC3 lipidation on multiple membranes to mitigate Mtb phagosome damage.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 13","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adt3311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A dyad of human-specific NBPF14 and NOTCH2NLB orchestrates cortical progenitor abundance crucial for human neocortex expansion

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-03-26 DOI: 10.1126/sciadv.ads7543

Nesil Eşiyok, Neringa Liutikaite, Christiane Haffner, Jula Peters, Sabrina Heide, Christina Eugster Oegema, Wieland B. Huttner, Michael Heide

{"title":"A dyad of human-specific NBPF14 and NOTCH2NLB orchestrates cortical progenitor abundance crucial for human neocortex expansion","authors":"Nesil Eşiyok, Neringa Liutikaite, Christiane Haffner, Jula Peters, Sabrina Heide, Christina Eugster Oegema, Wieland B. Huttner, Michael Heide","doi":"10.1126/sciadv.ads7543","DOIUrl":"10.1126/sciadv.ads7543","url":null,"abstract":"<div >We determined the roles of two coevolved and coexpressed human-specific genes, <i>NBPF14</i> and <i>NOTCH2NLB</i>, on the abundance of the cortical progenitors that underlie the evolutionary expansion of the neocortex, the seat of higher cognitive abilities in humans. Using automated microinjection into apical progenitors (APs) of embryonic mouse neocortex and electroporation of APs in chimpanzee cerebral organoids, we show that <i>NBPF14</i> promotes the delamination of AP progeny, by promoting oblique cleavage plane orientation during AP division, leading to increased abundance of the key basal progenitor type, basal radial glia. In contrast, <i>NOTCH2NLB</i> promotes AP proliferation, leading to expansion of the AP pool. When expressed together, <i>NBPF14</i> and <i>NOTCH2NLB</i> exert coordinated effects, resulting in expansion of basal progenitors while maintaining self-renewal of APs. Hence, these two human-specific genes orchestrate the behavior of APs, and the lineages of their progeny, in a manner essential for the evolutionary expansion of the human neocortex.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 13","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ads7543","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Catalyst-controlled regiodivergence and stereodivergence in formal cross-[4+2] cycloadditions: The unique effect of bismuth(III)

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-03-26 DOI: 10.1126/sciadv.adt5997

Qiumeng Hou, Chenxi Cai, Shuai-Jiang Liu, Wei Huang, Cheng Peng, Gu Zhan, Bo Han

{"title":"Catalyst-controlled regiodivergence and stereodivergence in formal cross-[4+2] cycloadditions: The unique effect of bismuth(III)","authors":"Qiumeng Hou, Chenxi Cai, Shuai-Jiang Liu, Wei Huang, Cheng Peng, Gu Zhan, Bo Han","doi":"10.1126/sciadv.adt5997","DOIUrl":"10.1126/sciadv.adt5997","url":null,"abstract":"<div >The [4+2] cycloaddition is crucial for constructing six-membered rings in pharmaceuticals and natural products. Cross-[4+2] cycloadditions offer greater product diversity than traditional diene-dienophile reactions due to multiple possible pathways. However, precise control over regio- and stereoselectivity for various isomers remains a great challenge. This study reports catalyst-controlled regiodivergent formal cross-cycloadditions of acyclic dienes and enones, significantly enhancing access to diverse pyrazole-fused spirooxindoles. Chiral phosphoric acid (CPA) catalysis enables endoselective [4+2] cycloadditions, while Bi(III) with a CPA ligand yields [2+4] products with high regio- and stereoselectivity. A Claisen rearrangement of the [2+4] adduct produces the exo-selective [4+2] product, further increasing stereochemical diversity and enabling the synthesis of six regio- and stereo-isomers from a single substrate set. DFT calculations reveal that Bi(III) reverses regioselectivity by repositioning reactants in the CPA pocket and stabilizing the enone oxygen’s negative charge. In addition, product <b>3as</b> demonstrates therapeutic potential against triple-negative breast cancer, with an IC<sub>50</sub> of 8.5 μM in MDA-MB-453 cells.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 13","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adt5997","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The emergence of human primordial germ cell–like cells in stem cell–derived gastruloids

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-03-26 DOI: 10.1126/sciadv.ado1350

Jitesh Neupane, Gabriele Lubatti, Theresa Gross-Thebing, Mayra Luisa Ruiz Tejada Segura, Richard Butler, Sargon Gross-Thebing, Sabine Dietmann, Antonio Scialdone, M. Azim Surani

{"title":"The emergence of human primordial germ cell–like cells in stem cell–derived gastruloids","authors":"Jitesh Neupane, Gabriele Lubatti, Theresa Gross-Thebing, Mayra Luisa Ruiz Tejada Segura, Richard Butler, Sargon Gross-Thebing, Sabine Dietmann, Antonio Scialdone, M. Azim Surani","doi":"10.1126/sciadv.ado1350","DOIUrl":"10.1126/sciadv.ado1350","url":null,"abstract":"<div >Most advances in early human postimplantation development depend on animal studies and stem cell–based embryo models. Here, we present self-organized three-dimensional human gastruloids (hGs) derived from embryonic stem cells. The transcriptome profile of day 3 hGs aligned with Carnegie stage 7 human gastrula, with cell types and differentiation trajectories consistent with human gastrulation. Notably, we observed the emergence of nascent primordial germ cell–like cells (PGCLCs), but without exogenous bone morphogenetic protein (BMP) signaling, which is essential for the PGCLC fate. A mutation in the <i>ISL1</i> gene affects amnion-like cells and leads to a loss of PGCLCs; the addition of exogenous BMP2 rescues the PGCLC fate, indicating that the amnion may provide endogenous BMP signaling. Our model of early human embryogenesis will enable further exploration of the germ line and other early human lineages.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 13","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ado1350","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Histone modification–driven structural remodeling unleashes DNMT3B in DNA methylation

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-03-26 DOI: 10.1126/sciadv.adu8116

Chao-Cheng Cho, Hsun-Ho Huang, Bo-Chen Jiang, Wei-Zen Yang, Yi-Ning Chen, Hanna S. Yuan

{"title":"Histone modification–driven structural remodeling unleashes DNMT3B in DNA methylation","authors":"Chao-Cheng Cho, Hsun-Ho Huang, Bo-Chen Jiang, Wei-Zen Yang, Yi-Ning Chen, Hanna S. Yuan","doi":"10.1126/sciadv.adu8116","DOIUrl":"10.1126/sciadv.adu8116","url":null,"abstract":"<div >The DNA methyltransferase 3B (DNMT3B) plays a vital role in shaping DNA methylation patterns during mammalian development. DNMT3B is intricately regulated by histone H3 modifications, yet the dynamic interplay between DNMT3B and histone modifications remains enigmatic. Here, we demonstrate that the PWWP (proline-tryptophan-tryptophan-proline) domain within DNMT3B exhibits remarkable dynamics that enhances the enzyme’s methyltransferase activity upon interactions with a modified histone H3 peptide (H3K4<sup>me0</sup>K36<sup>me3</sup>). In the presence of H3K4<sup>me0</sup>K36<sup>me3</sup>, both the PWWP and ADD (ATRX-DNMT3-DNMT3L) domains transition from autoinhibitory to active conformations. In this active state, the PWWP domain most often aligns closely with the catalytic domain, allowing for simultaneous interactions with H3 and DNA to stimulate DNA methylation. The prostate cancer–associated DNMT3B R545C mutant is even more dynamic and susceptible to adopting the active conformation, resulting in aberrant DNA hypermethylation. Our study suggests the mechanism by which conformational rearrangements in DNMT3B are triggered by histone modifications, ultimately unleashing its activity in DNA methylation.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 13","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adu8116","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retinal gene therapy for Stargardt disease with dual AAV intein vectors is both safe and effective in large animal models

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-03-26 DOI: 10.1126/sciadv.adt9354

Rita Ferla, Eugenio Pugni, Mariangela Lupo, Paola Tiberi, Federica Fioretto, Andrea Perota, Roberto Duchi, Irina Lagutina, Carlo Gesualdo, Settimio Rossi, Domenico Ventrella, Alberto Elmi, Benjamin McClinton, Carmel Toomes, Tongzhou Xu, Robert S. Molday, Enrico M. Surace, Francesca Simonelli, Maria L. Bacci, Cesare Galli, Muhammad A. Memon, Naveed Shams, Alberto Auricchio, Ivana Trapani

{"title":"Retinal gene therapy for Stargardt disease with dual AAV intein vectors is both safe and effective in large animal models","authors":"Rita Ferla, Eugenio Pugni, Mariangela Lupo, Paola Tiberi, Federica Fioretto, Andrea Perota, Roberto Duchi, Irina Lagutina, Carlo Gesualdo, Settimio Rossi, Domenico Ventrella, Alberto Elmi, Benjamin McClinton, Carmel Toomes, Tongzhou Xu, Robert S. Molday, Enrico M. Surace, Francesca Simonelli, Maria L. Bacci, Cesare Galli, Muhammad A. Memon, Naveed Shams, Alberto Auricchio, Ivana Trapani","doi":"10.1126/sciadv.adt9354","DOIUrl":"10.1126/sciadv.adt9354","url":null,"abstract":"<div >Retinal gene therapy using dual adeno-associated viral (AAV) intein vectors can be applied to genetic forms of blindness caused by mutations in genes with coding sequences that exceed single AAV cargo capacity, such as Stargardt disease (STGD1), the most common inherited macular dystrophy. In view of clinical translation of dual AAV intein vectors, here we set to evaluate both the efficiency and safety of their subretinal administration in relevant large animal models. Accordingly, we have developed the first pig model of STGD1, which we found to accumulate lipofuscin similarly to patients. This accumulation is significantly reduced upon subretinal administration of dual AAV intein vectors whose safety and pharmacodynamics we then tested in nonhuman primates, which showed modest and reversible inflammation as well as high levels of photoreceptor transduction. This bodes well for further clinical translation of dual AAV intein vectors in patients with STGD1 as well as for other blinding diseases that require the delivery of large genes.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 13","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adt9354","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Demographic bias of expert-level vision-language foundation models in medical imaging

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-03-26 DOI: 10.1126/sciadv.adq0305

Yuzhe Yang, Yujia Liu, Xin Liu, Avanti Gulhane, Domenico Mastrodicasa, Wei Wu, Edward J. Wang, Dushyant Sahani, Shwetak Patel

{"title":"Demographic bias of expert-level vision-language foundation models in medical imaging","authors":"Yuzhe Yang, Yujia Liu, Xin Liu, Avanti Gulhane, Domenico Mastrodicasa, Wei Wu, Edward J. Wang, Dushyant Sahani, Shwetak Patel","doi":"10.1126/sciadv.adq0305","DOIUrl":"10.1126/sciadv.adq0305","url":null,"abstract":"<div >Advances in artificial intelligence (AI) have achieved expert-level performance in medical imaging applications. Notably, self-supervised vision-language foundation models can detect a broad spectrum of pathologies without relying on explicit training annotations. However, it is crucial to ensure that these AI models do not mirror or amplify human biases, disadvantaging historically marginalized groups such as females or Black patients. In this study, we investigate the algorithmic fairness of state-of-the-art vision-language foundation models in chest x-ray diagnosis across five globally sourced datasets. Our findings reveal that compared to board-certified radiologists, these foundation models consistently underdiagnose marginalized groups, with even higher rates seen in intersectional subgroups such as Black female patients. Such biases present over a wide range of pathologies and demographic attributes. Further analysis of the model embedding uncovers its substantial encoding of demographic information. Deploying medical AI systems with biases can intensify preexisting care disparities, posing potential challenges to equitable healthcare access and raising ethical questions about their clinical applications.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 13","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq0305","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteogenomic discovery of RB1-defective phenocopy in cancer predicts disease outcome, response to treatment, and therapeutic targets

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-03-26 DOI: 10.1126/sciadv.adq9495

Jacopo Iacovacci, Rachel Brough, Fatemeh Ahmadi Moughari, John Alexander, Harriet Kemp, Andrew N. J. Tutt, Rachael Natrajan, Christopher J. Lord, Syed Haider

{"title":"Proteogenomic discovery of RB1-defective phenocopy in cancer predicts disease outcome, response to treatment, and therapeutic targets","authors":"Jacopo Iacovacci, Rachel Brough, Fatemeh Ahmadi Moughari, John Alexander, Harriet Kemp, Andrew N. J. Tutt, Rachael Natrajan, Christopher J. Lord, Syed Haider","doi":"10.1126/sciadv.adq9495","DOIUrl":"10.1126/sciadv.adq9495","url":null,"abstract":"<div >Genomic defects caused by truncating mutations or deletions in the Retinoblastoma tumor suppressor gene (<i>RB1</i>) are frequently observed in many cancer types leading to dysregulation of the RB pathway. Here, we propose an integrative proteogenomic approach that predicts cancers with dysregulation in the RB pathway. A subset of these cancers, which we term as “RBness,” lack <i>RB1</i> genomic defects and yet phenocopy the transcriptional profile of <i>RB1</i>-defective cancers. We report RBness as a pan-cancer phenomenon, associated with patient outcome and chemotherapy response in multiple cancer types, and predictive of CDK4/6 inhibitor response in estrogen-positive breast cancer. Using RNA interference and a CRISPR-Cas9 screen in isogenic models, we find that RBness cancers also phenocopy synthetic lethal vulnerabilities of cells with <i>RB1</i> genomic defects. In summary, our findings suggest that dysregulation of the RB pathway in cancers lacking <i>RB1</i> genomic defects provides a molecular rationale for how these cancers could be treated.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 13","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq9495","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HMCES corrupts replication fork stability during base excision repair in homologous recombination–deficient cells

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-03-26 DOI: 10.1126/sciadv.ads3227

María José Peña-Gómez, Yaiza Rodríguez-Martín, Marta del Rio Oliva, Yodhara Wijesekara Hanthi, Sara Berrada, Raimundo Freire, Jean Yves Masson, José Carlos Reyes, Vincenzo Costanzo, Iván V. Rosado

{"title":"HMCES corrupts replication fork stability during base excision repair in homologous recombination–deficient cells","authors":"María José Peña-Gómez, Yaiza Rodríguez-Martín, Marta del Rio Oliva, Yodhara Wijesekara Hanthi, Sara Berrada, Raimundo Freire, Jean Yves Masson, José Carlos Reyes, Vincenzo Costanzo, Iván V. Rosado","doi":"10.1126/sciadv.ads3227","DOIUrl":"10.1126/sciadv.ads3227","url":null,"abstract":"<div >Apurinic/apyrimidinic (AP) sites and single-strand breaks arising from base excision repair (BER) during the misincorporation of damaged nucleobases may hinder replication fork stability in homologous recombination–deficient (HRD) cells. At templated AP sites, cross-links between the DNA and 5-hydroxymethylcytosine binding, embryonic stem cell–specific (HMCES) regulate replication fork speed, avoiding cytotoxic double-strand breaks. While the role of HMCES at the template DNA strand is well studied, its effects on nascent DNA are not. We provide evidence that HMCES–DNA-protein cross-links (DPCs) are detrimental to the BER-mediated removal of 5-hydroxymethyl-2′-deoxycytidine (5hmdC)–derived 5-hydroxymethyl-2′-deoxyuridine from replication forks. HRD cells have heightened HMCES-DPCs, which increase further upon 5hmdC exposure, suggesting that HMCES binds both spontaneous and 5hmdC-induced AP sites. HMCES depletion substantially suppresses 5hmdC-mediated replication fork defects, chromosomal aberrations, and cell death in HRD cells. This reveals that HMCES-DPCs are a source of BER-initiated single-stranded DNA gaps, which indicates that endogenous DPCs contribute to genomic instability in HRD tumors.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 13","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ads3227","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An in vivo screen identifies NAT10 as a master regulator of brain metastasis

IF 11.7 1区综合性期刊

Science Advances Pub Date : 2025-03-26 DOI: 10.1126/sciadv.ads6021

Jocelyn F. Chen, Peng Xu, Wesley L. Cai, Huacui Chen, Emily Wingrove, Xiaojian Shi, Wenxue Li, Giulia Biancon, Meiling Zhang, Amer Balabaki, Ethan D. Krop, Elianna Asare, Yangyi Zhang, Mingzhu Yin, Toma Tebaldi, Jordan L. Meier, Thomas F. Westbrook, Stephanie Halene, Yansheng Liu, Hongying Shen, Don X. Nguyen, Qin Yan

{"title":"An in vivo screen identifies NAT10 as a master regulator of brain metastasis","authors":"Jocelyn F. Chen, Peng Xu, Wesley L. Cai, Huacui Chen, Emily Wingrove, Xiaojian Shi, Wenxue Li, Giulia Biancon, Meiling Zhang, Amer Balabaki, Ethan D. Krop, Elianna Asare, Yangyi Zhang, Mingzhu Yin, Toma Tebaldi, Jordan L. Meier, Thomas F. Westbrook, Stephanie Halene, Yansheng Liu, Hongying Shen, Don X. Nguyen, Qin Yan","doi":"10.1126/sciadv.ads6021","DOIUrl":"10.1126/sciadv.ads6021","url":null,"abstract":"<div >Emerging evidence has shown that epigenetic regulation plays a fundamental role in cancer metastasis, the major cause of cancer-related deaths. Here, we conducted an in vivo screen for vulnerabilities of brain metastasis and identified <i>N</i>-acetyltransferase 10 (NAT10) as a driver of brain metastasis. Knockdown of NAT10 restrains cancer cell proliferation and migration in vitro and tumor growth and brain metastasis in vivo. The poorly characterized RNA helicase domain of NAT10 is critical for cell growth in vitro, while both RNA helicase and NAT domains are essential for primary tumor growth and brain metastasis in vivo. Mechanically, NAT10 promotes the expression of 3-phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), two enzymes for serine biosynthesis implicated in brain metastasis. Silencing <i>PHGDH</i> or <i>PSAT1</i> in metastatic breast cancer cells inhibits their growth in the serine/glycine-limited condition, phenocopying the effects of NAT10 depletion. These findings establish NAT10 as a key regulator of brain metastasis and nominate NAT10 as a target for treating metastasis.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 13","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ads6021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0