Molecular Systems Biology最新文献_第4页

Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures. 亨廷顿蛋白的多表位免疫捕获揭示纹状体选择性分子特征。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-05-01 Epub Date: 2025-04-01 DOI: 10.1038/s44320-025-00096-3

Joshua L Justice, Todd M Greco, Josiah E Hutton, Tavis J Reed, Megan L Mair, Juan Botas, Ileana M Cristea

{"title":"Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures.","authors":"Joshua L Justice, Todd M Greco, Josiah E Hutton, Tavis J Reed, Megan L Mair, Juan Botas, Ileana M Cristea","doi":"10.1038/s44320-025-00096-3","DOIUrl":"10.1038/s44320-025-00096-3","url":null,"abstract":"Huntington's disease (HD) is a debilitating neurodegenerative disorder affecting an individual's cognitive and motor abilities. HD is caused by a mutation in the huntingtin gene producing a toxic polyglutamine-expanded protein (mHTT) and leading to degeneration in the striatum and cortex. Yet, the molecular signatures that underlie tissue-specific vulnerabilities remain unclear. Here, we investigate this aspect by leveraging multi-epitope protein interaction assays, subcellular fractionation, thermal proteome profiling, and genetic modifier assays. The use of human cell, mouse, and fly models afforded capture of distinct subcellular pools of epitope-enriched and tissue-dependent interactions linked to dysregulated cellular pathways and disease relevance. We established an HTT association with nearly all subunits of the transcriptional regulatory Mediator complex (20/26), with preferential enrichment of MED15 in the tail domain. Using HD and KO models, we find HTT modulates the subcellular localization and assembly of the Mediator. We demonstrated striatal enriched and functional interactions with regulators of calcium homeostasis and chromatin remodeling, whose disease relevance was supported by HD fly genetic modifiers assays. Altogether, we offer insights into tissue- and localization-dependent (m)HTT functions and pathobiology.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"492-522"},"PeriodicalIF":8.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spatial entropy drives the maintenance and dissemination of transferable plasmids. 空间熵驱动可转移质粒的维持和传播。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-04-29 DOI: 10.1038/s44320-025-00110-8

Wenzhi Xue, Juken Hong, Runmeng Zhao, Huaxiong Yao, Yi Zhang, Zhuojun Dai, Teng Wang

{"title":"Spatial entropy drives the maintenance and dissemination of transferable plasmids.","authors":"Wenzhi Xue, Juken Hong, Runmeng Zhao, Huaxiong Yao, Yi Zhang, Zhuojun Dai, Teng Wang","doi":"10.1038/s44320-025-00110-8","DOIUrl":"https://doi.org/10.1038/s44320-025-00110-8","url":null,"abstract":"The dissemination of transferable plasmids, a major type of mobile genetic elements (MGEs), is one main driver of antibiotic resistance outbreaks. While the plasmid persistence condition in well-mixed environments has been extensively studied, most microbiota in nature are spatially heterogeneous. However, our knowledge regarding how spatial landscape shapes plasmid maintenance and dissemination remains limited. Here we establish a theoretical framework describing plasmid spread over a metacommunity of multiple patches. By analyzing the gene flow dynamics on randomly generated landscapes, we show that plasmid survival and dispersal are dictated by a simple feature of the landscape, spatial entropy. Reducing entropy speeds up plasmid range expansion and allows the global maintenance of many plasmids that are predicted to be lost by classic theories. The entropy's effects are experimentally validated in E. coli metacommunities transferring a conjugative plasmid. We further examine a vast collection of prokaryotic genomes and show that prokaryotes from low-entropy environments indeed carry more abundant MGEs and antibiotic resistance genes. Our work provides critical insights into the management and control of antimicrobial resistance.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteomics of colorectal tumors identifies the role of CAVIN1 in tumor relapse. 结直肠肿瘤的蛋白质组学鉴定CAVIN1在肿瘤复发中的作用。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-04-23 DOI: 10.1038/s44320-025-00102-8

Ana Martinez-Val, Leander Van der Hoeven, Dorte B Bekker-Jensen, Margarita Melnikova Jørgensen, Jesper Nors, Giulia Franciosa, Claus L Andersen, Jesper B Bramsen, Jesper V Olsen

{"title":"Proteomics of colorectal tumors identifies the role of CAVIN1 in tumor relapse.","authors":"Ana Martinez-Val, Leander Van der Hoeven, Dorte B Bekker-Jensen, Margarita Melnikova Jørgensen, Jesper Nors, Giulia Franciosa, Claus L Andersen, Jesper B Bramsen, Jesper V Olsen","doi":"10.1038/s44320-025-00102-8","DOIUrl":"https://doi.org/10.1038/s44320-025-00102-8","url":null,"abstract":"Colorectal cancer molecular signatures derived from omics data can be employed to stratify CRC patients and aid decisions about therapies or evaluate prognostic outcome. However, molecular biomarkers for identification of patients at increased risk of disease relapse are currently lacking. Here, we present a comprehensive multi-omics analysis of a Danish colorectal cancer tumor cohort composed of 412 biopsies from tumors of 371 patients diagnosed at TNM stage II or III. From mass spectrometry-based patient proteome profiles, we classified the tumors into four molecular subtypes, including a mesenchymal-like subtype. As the mesenchymal-rich tumors are known to represent the most invasive and metastatic phenotype, we focused on the protein signature defining this subtype to evaluate their potential as relapse risk markers. Among signature-specific proteins, we followed-up Caveolae-Associated Protein-1 (CAVIN1) and demonstrated its role in tumor progression in a 3D in vitro model of colorectal cancer. Compared to previous omics analyses of CRC, our multi-omics classification provided deeper insights into EMT in cancer cells with stronger correlations with risk of relapse.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BaCoN (Balanced Correlation Network) improves prediction of gene buffering. BaCoN （Balanced Correlation Network）改进了基因缓冲的预测。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-04-22 DOI: 10.1038/s44320-025-00103-7

Thomas Rohde, Talip Yasir Demirtas, Sebastian Süsser, Angela Helen Shaw, Manuel Kaulich, Maximilian Billmann

{"title":"BaCoN (Balanced Correlation Network) improves prediction of gene buffering.","authors":"Thomas Rohde, Talip Yasir Demirtas, Sebastian Süsser, Angela Helen Shaw, Manuel Kaulich, Maximilian Billmann","doi":"10.1038/s44320-025-00103-7","DOIUrl":"https://doi.org/10.1038/s44320-025-00103-7","url":null,"abstract":"Buffering between genes, where one gene can compensate for the loss of another gene, is fundamental for robust cellular functions. While experimentally testing all possible gene pairs is infeasible, gene buffering can be predicted genome-wide under the assumption that a gene's buffering capacity depends on its expression level and its absence primes a severe fitness phenotype of the buffered gene. We developed BaCoN (Balanced Correlation Network), a post hoc unsupervised correction method that amplifies specific signals in expression-vs-fitness correlation networks. We quantified 147 million potential buffering relationships by associating CRISPR-Cas9-screening fitness effects with transcriptomic data across 1019 Cancer Dependency Map (DepMap) cell lines. BaCoN outperformed state-of-the-art methods, including multiple linear regression based on our compiled gene buffering prediction metrics. Combining BaCoN with batch correction or Cholesky data whitening further boosts predictive performance. We characterized 808 high-confidence buffering predictions and found that in contrast to buffering gene pairs overall, buffering paralogs were on different chromosomes. BaCoN performance increases with more screens and genes considered, making it a valuable tool for gene buffering predictions from the growing DepMap.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Circadian clock features define novel subtypes among breast cancer cells and shape drug sensitivity. 生物钟特征定义了乳腺癌细胞中的新亚型并形成了药物敏感性。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-04-01 Epub Date: 2025-02-24 DOI: 10.1038/s44320-025-00092-7

Carolin Ector, Jeff Didier, Sébastien De Landtsheer, Malthe S Nordentoft, Christoph Schmal, Ulrich Keilholz, Hanspeter Herzel, Achim Kramer, Thomas Sauter, Adrián E Granada

{"title":"Circadian clock features define novel subtypes among breast cancer cells and shape drug sensitivity.","authors":"Carolin Ector, Jeff Didier, Sébastien De Landtsheer, Malthe S Nordentoft, Christoph Schmal, Ulrich Keilholz, Hanspeter Herzel, Achim Kramer, Thomas Sauter, Adrián E Granada","doi":"10.1038/s44320-025-00092-7","DOIUrl":"10.1038/s44320-025-00092-7","url":null,"abstract":"The circadian clock regulates key physiological processes, including cellular responses to DNA damage. Circadian-based therapeutic strategies optimize treatment timing to enhance drug efficacy and minimize side effects, offering potential for precision cancer treatment. However, applying these strategies in cancer remains limited due to a lack of understanding of the clock's function across cancer types and incomplete insights into how the circadian clock affects drug responses. To address this, we conducted deep circadian phenotyping across a panel of breast cancer cell lines. Observing diverse circadian dynamics, we characterized metrics to assess circadian rhythm strength and stability in vitro. This led to the identification of four distinct circadian-based phenotypes among 14 breast cancer cell models: functional, weak, unstable, and dysfunctional clocks. Furthermore, we demonstrate that the circadian clock plays a critical role in shaping pharmacological responses to various anti-cancer drugs and we identify circadian features descriptive of drug sensitivity. Collectively, our findings establish a foundation for implementing circadian-based treatment strategies in breast cancer, leveraging clock phenotypes and drug sensitivity patterns to optimize therapeutic outcomes.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"315-340"},"PeriodicalIF":8.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages. 单核细胞源性巨噬细胞接种SARS-CoV-2 mRNA的持续表观遗传记忆

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-04-01 Epub Date: 2025-03-25 DOI: 10.1038/s44320-025-00093-6

Alexander Simonis, Sebastian J Theobald, Anna E Koch, Ram Mummadavarapu, Julie M Mudler, Andromachi Pouikli, Ulrike Göbel, Richard Acton, Sandra Winter, Alexandra Albus, Dmitriy Holzmann, Marie-Christine Albert, Michael Hallek, Henning Walczak, Thomas Ulas, Manuel Koch, Peter Tessarz, Robert Hänsel-Hertsch, Jan Rybniker

{"title":"Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages.","authors":"Alexander Simonis, Sebastian J Theobald, Anna E Koch, Ram Mummadavarapu, Julie M Mudler, Andromachi Pouikli, Ulrike Göbel, Richard Acton, Sandra Winter, Alexandra Albus, Dmitriy Holzmann, Marie-Christine Albert, Michael Hallek, Henning Walczak, Thomas Ulas, Manuel Koch, Peter Tessarz, Robert Hänsel-Hertsch, Jan Rybniker","doi":"10.1038/s44320-025-00093-6","DOIUrl":"10.1038/s44320-025-00093-6","url":null,"abstract":"Immune memory plays a critical role in the development of durable antimicrobial immune responses. How precisely mRNA vaccines train innate immune cells to shape protective host defense mechanisms remains unknown. Here we show that SARS-CoV-2 mRNA vaccination significantly establishes histone H3 lysine 27 acetylation (H3K27ac) at promoters of human monocyte-derived macrophages, suggesting epigenetic memory. However, we found that two consecutive vaccinations were required for the persistence of H3K27ac, which matched with pro-inflammatory innate immune-associated transcriptional changes and antigen-mediated cytokine secretion. H3K27ac at promoter regions were preserved for six months and a single mRNA booster vaccine potently restored their levels and release of macrophage-derived cytokines. Interestingly, we found that H3K27ac at promoters is enriched for G-quadruplex DNA secondary structure-forming sequences in macrophage-derived nucleosome-depleted regions, linking epigenetic memory to nucleic acid structure. Collectively, these findings reveal that mRNA vaccines induce a highly dynamic and persistent training of innate immune cells enabling a sustained pro-inflammatory immune response.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"341-360"},"PeriodicalIF":8.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pulsed stimuli enable p53 phase resetting to synchronize single cells and modulate cell fate. 脉冲刺激使p53阶段重置同步单细胞和调节细胞命运。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-04-01 Epub Date: 2025-03-03 DOI: 10.1038/s44320-025-00091-8

Harish Venkatachalapathy, Samuel Dallon, Zhilin Yang, Samira M Azarin, Casim A Sarkar, Eric Batchelor

{"title":"Pulsed stimuli enable p53 phase resetting to synchronize single cells and modulate cell fate.","authors":"Harish Venkatachalapathy, Samuel Dallon, Zhilin Yang, Samira M Azarin, Casim A Sarkar, Eric Batchelor","doi":"10.1038/s44320-025-00091-8","DOIUrl":"10.1038/s44320-025-00091-8","url":null,"abstract":"Oscillatory p53 expression occurs in individual cells responding to DNA breaks. While the majority of cells exhibit the same qualitative response, quantitative features of the oscillations (e.g., amplitude or period) can be highly variable between cells, generating heterogeneity in downstream cell fate responses. Since heterogeneity can be detrimental to therapies based on DNA damage, methods to induce synchronization of p53 oscillations across cells in a population have the potential to generate more predictable responses to DNA-damaging treatments. Using mathematical modeling and time-lapse microscopy, we demonstrated that p53 oscillations can be synchronized through the phenomenon of phase resetting. Surprisingly, p53 oscillations were synchronized over a wider range of damage-induction frequencies than predicted computationally. Recapitulating the range of synchronizing frequencies required, non-intuitively, a less robust oscillator. We showed that p53 phase resetting altered the expression of downstream targets responsible for cell fate depending on target mRNA stability. This study demonstrates that p53 oscillations can be phase reset and highlights the potential of driving p53 dynamics to reduce cellular variability and synchronize cell fate responses to DNA damage.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"390-412"},"PeriodicalIF":8.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Abundant clock proteins point to missing molecular regulation in the plant circadian clock. 丰富的时钟蛋白表明植物昼夜节律时钟中缺少分子调控。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-04-01 Epub Date: 2025-02-20 DOI: 10.1038/s44320-025-00086-5

Uriel Urquiza-García, Nacho Molina, Karen J Halliday, Andrew J Millar

{"title":"Abundant clock proteins point to missing molecular regulation in the plant circadian clock.","authors":"Uriel Urquiza-García, Nacho Molina, Karen J Halliday, Andrew J Millar","doi":"10.1038/s44320-025-00086-5","DOIUrl":"10.1038/s44320-025-00086-5","url":null,"abstract":"Understanding the biochemistry behind whole-organism traits such as flowering time is a longstanding challenge, where mathematical models are critical. Very few models of plant gene circuits use the absolute units required for comparison to biochemical data. We refactor two detailed models of the plant circadian clock from relative to absolute units. Using absolute RNA quantification, a simple model predicted abundant clock protein levels in Arabidopsis thaliana, up to 100,000 proteins per cell. NanoLUC reporter protein fusions validated the predicted levels of clock proteins in vivo. Recalibrating the detailed models to these protein levels estimated their DNA-binding dissociation constants (Kd). We estimate the same Kd from multiple results in vitro, extending the method to any promoter sequence. The detailed models simulated the Kd range estimated from LUX DNA-binding in vitro but departed from the data for CCA1 binding, pointing to further circadian mechanisms. Our analytical and experimental methods should transfer to understand other plant gene regulatory networks, potentially including the natural sequence variation that contributes to evolutionary adaptation.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"361-389"},"PeriodicalIF":8.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhanced flux potential analysis links changes in enzyme expression to metabolic flux. 增强通量势分析将酶表达的变化与代谢通量联系起来。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-04-01 Epub Date: 2025-02-17 DOI: 10.1038/s44320-025-00090-9

Xuhang Li, Albertha J M Walhout, L Safak Yilmaz

{"title":"Enhanced flux potential analysis links changes in enzyme expression to metabolic flux.","authors":"Xuhang Li, Albertha J M Walhout, L Safak Yilmaz","doi":"10.1038/s44320-025-00090-9","DOIUrl":"10.1038/s44320-025-00090-9","url":null,"abstract":"Algorithms that constrain metabolic network models with enzyme levels to predict metabolic activity assume that changes in enzyme levels are indicative of flux variations. However, metabolic flux can also be regulated by other mechanisms such as allostery and mass action. To systematically explore the relationship between fluctuations in enzyme expression and flux, we combine available yeast proteomic and fluxomic data to reveal that flux changes can be best predicted from changes in enzyme levels of pathways, rather than the whole network or only cognate reactions. We implement this principle in an 'enhanced flux potential analysis' (eFPA) algorithm that integrates enzyme expression data with metabolic network architecture to predict relative flux levels of reactions including those regulated by other mechanisms. Applied to human data, eFPA consistently predicts tissue metabolic function using either proteomic or transcriptomic data. Additionally, eFPA efficiently handles data sparsity and noisiness, generating robust flux predictions with single-cell gene expression data. Our approach outperforms alternatives by striking an optimal balance, evaluating enzyme expression at pathway level, rather than either single-reaction or whole-network levels.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"413-445"},"PeriodicalIF":8.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response. 吉西他滨和ATR抑制剂通过阻断DNA损伤反应协同杀死PDAC细胞。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-03-01 Epub Date: 2025-01-21 DOI: 10.1038/s44320-025-00085-6

Stefanie Höfer, Larissa Frasch, Sarah Brajkovic, Kerstin Putzker, Joe Lewis, Hendrik Schürmann, Valentina Leone, Amirhossein Sakhteman, Matthew The, Florian P Bayer, Julian Müller, Firas Hamood, Jens T Siveke, Maximilian Reichert, Bernhard Kuster

{"title":"Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response.","authors":"Stefanie Höfer, Larissa Frasch, Sarah Brajkovic, Kerstin Putzker, Joe Lewis, Hendrik Schürmann, Valentina Leone, Amirhossein Sakhteman, Matthew The, Florian P Bayer, Julian Müller, Firas Hamood, Jens T Siveke, Maximilian Reichert, Bernhard Kuster","doi":"10.1038/s44320-025-00085-6","DOIUrl":"10.1038/s44320-025-00085-6","url":null,"abstract":"The DNA-damaging agent Gemcitabine (GEM) is a first-line treatment for pancreatic cancer, but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs, including kinase inhibitors, but the experimental evidence for such rationale is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 146 clinical inhibitors and observed strong synergy for the ATR kinase inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway, including phosphorylated pS468 of CHEK1, as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"231-253"},"PeriodicalIF":8.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0