IF 3.2

NAR cancer Pub Date : 2025-09-03 eCollection Date: 2025-09-01 DOI: 10.1093/narcan/zcaf027

Carlos Peula, Margalida Esteva-Socias, Kanchan Kumari, Erik Dassi, Francesca Aguilo

引用次数: 0

Neural interaction explainable AI predicts drug response across cancers. 神经相互作用可解释的AI预测癌症的药物反应。

IF 3.2

NAR cancer Pub Date : 2025-09-03 eCollection Date: 2025-09-01 DOI: 10.1093/narcan/zcaf029

Philipp Keyl, Julius Keyl, Andreas Mock, Gabriel Dernbach, Liliana H Mochmann, Niklas Kiermeyer, Philipp Jurmeister, Michael Bockmayr, Roland F Schwarz, Grégoire Montavon, Klaus-Robert Müller, Frederick Klauschen

{"title":"Neural interaction explainable AI predicts drug response across cancers.","authors":"Philipp Keyl, Julius Keyl, Andreas Mock, Gabriel Dernbach, Liliana H Mochmann, Niklas Kiermeyer, Philipp Jurmeister, Michael Bockmayr, Roland F Schwarz, Grégoire Montavon, Klaus-Robert Müller, Frederick Klauschen","doi":"10.1093/narcan/zcaf029","DOIUrl":"10.1093/narcan/zcaf029","url":null,"abstract":"Personalized treatment selection is crucial for cancer patients due to the high variability in drug response. While actionable mutations can increasingly inform treatment decisions, most therapies still rely on population-based approaches. Here, we introduce neural interaction explainable AI (NeurixAI), an explainable and highly scalable deep learning framework that models drug-gene interactions and identifies transcriptomic patterns linked with drug response. Trained on data from 546 646 drug perturbation experiments involving 1135 drugs and molecular profiles from 476 tumors, NeurixAI accurately predicted treatment responses for 272 targeted and 30 chemotherapeutic drugs in unseen tumor samples (Spearman's rho >0.2), maintaining high performance on an external validation set. Additionally, NeurixAI identified the anticancer potential of 160 repurposed non-cancer drugs. Using explainable artificial intelligence (xAI), our framework uncovered key genes influencing drug response at the individual tumor level and revealed both known and novel mechanisms of drug resistance. These findings demonstrate the potential of integrating transcriptomics with xAI to optimize cancer treatment, enable drug repurposing, and identify new therapeutic targets.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 3","pages":"zcaf029"},"PeriodicalIF":3.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ABL1-mediated tyrosine phosphorylation of SYCP2 contributes to transcription-coupled homologous recombination and platinum resistance in ovarian cancer. abl1介导的SYCP2酪氨酸磷酸化有助于卵巢癌转录偶联同源重组和铂耐药。

IF 3.2

NAR cancer Pub Date : 2025-09-03 eCollection Date: 2025-09-01 DOI: 10.1093/narcan/zcaf031

Boya Gao, Xudong Wang, Melissa Long, Fengqi Zhang, Yumin Wang, Raj Kumar, Irva Veillard, Bo R Rueda, Oladapo Yeku, Li Lan

{"title":"ABL1-mediated tyrosine phosphorylation of SYCP2 contributes to transcription-coupled homologous recombination and platinum resistance in ovarian cancer.","authors":"Boya Gao, Xudong Wang, Melissa Long, Fengqi Zhang, Yumin Wang, Raj Kumar, Irva Veillard, Bo R Rueda, Oladapo Yeku, Li Lan","doi":"10.1093/narcan/zcaf031","DOIUrl":"10.1093/narcan/zcaf031","url":null,"abstract":"Treatment of patients with platinum-resistant ovarian cancer is a major clinical challenge. We found that high expression of a meiotic protein, Synaptonemal Complex Protein 2 (SYCP2), is associated with platinum resistance and tyrosine kinase ABL1 inhibitor sensitivity in ovarian cancer. We demonstrate that tyrosine kinase ABL1 inhibitors inhibit cancer cell proliferation more efficiently in ovarian cancer cell lines with SYCP2 overexpression. Moreover, ABL1 inhibition effectively prevents tumor growth in vivo. Mechanistically, we identified a phosphorylation motif [RK]-x(2,3)-[DE]-x(2,3)-Y in SYCP2 and found that abolishing ABL1-mediated phosphorylation of SYCP2 at its tyrosine (Y) 739 within this motif renders ABL1 sensitivity of cancer cells. Importantly, ABL1 and SYCP2 colocalize at sites of R-loops after damage and promote transcription-coupled homologous recombination. Moreover, ABL1-mediated Y739 phosphorylation of SYCP2 promotes function of SYCP2 at sites of R-loops by facilitating RAD51 localization and repair, contributing to ovarian cancer cell survival. Overall, these findings highlight a novel therapeutic mechanism where ABL1 inhibitors induce cell death in platinum-resistant ovarian cancer by impairing transcription-coupled homologous recombination repair.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 3","pages":"zcaf031"},"PeriodicalIF":3.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","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 aflatoxin B₁-induced formamidopyrimidine adduct is repaired by transcription-coupled nucleotide excision repair in human cells. 黄曲霉毒素b1诱导的甲酰胺嘧啶加合物通过转录偶联核苷酸切除修复。

IF 3.2

NAR cancer Pub Date : 2025-09-03 eCollection Date: 2025-09-01 DOI: 10.1093/narcan/zcaf030

Daniel J Laverty, Rachana Tomar, Sophie Erlich, Michael P Stone, Zachary D Nagel

{"title":"The aflatoxin B1-induced formamidopyrimidine adduct is repaired by transcription-coupled nucleotide excision repair in human cells.","authors":"Daniel J Laverty, Rachana Tomar, Sophie Erlich, Michael P Stone, Zachary D Nagel","doi":"10.1093/narcan/zcaf030","DOIUrl":"10.1093/narcan/zcaf030","url":null,"abstract":"The mycotoxin, aflatoxin B1 (AFB1), is a potent mutagen that contaminates agricultural food supplies. After ingestion, AFB1 is oxidized into a reactive electrophile that alkylates DNA, forming bulky lesions such as the genotoxic formamidopyrimidine lesion, AFB1-Fapy dG. This lesion is mainly repaired by nucleotide excision repair (NER) in bacteria; however, in humans the picture is less clear. We report a plasmid-based host cell reactivation assay containing a site-specific AFB1-Fapy dG lesion and present evidence that this lesion is mainly repaired by transcription-coupled NER (TC-NER) in human cells. Using a combination of isogenic knockout cell lines and immortalized fibroblasts from xeroderma pigmentosum and Cockayne syndrome patients, we show that the TC-NER factors CSA, CSB, and UVSSA are required for efficient AFB1-Fapy dG repair, while the global-genome NER protein, XPC, is dispensable. Furthermore, knockout of CSB or UVSSA impairs AFB1-Fapy dG repair to a similar degree as knockout of the core NER nuclease, XPF. Our data indicate that TC-NER is the major repair pathway for AFB1-Fapy dG adducts in human cells.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 3","pages":"zcaf030"},"PeriodicalIF":3.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Loss of ribosomal protein uL14 enables tumor escape from T cell immunosurveillance. 核糖体蛋白uL14的缺失使肿瘤逃避T细胞免疫监视。

IF 3.2

NAR cancer Pub Date : 2025-08-30 eCollection Date: 2025-09-01 DOI: 10.1093/narcan/zcaf024

Anna Dopler, Edwin S Kyei-Baffour, Mandy Kerkhoff, Ferhat Alkan, Yuval Malka, Kelly Hoefakker, Rob van der Kammen, Liesbeth Hoekman, Onno Bleijerveld, Antonia Bradaric, Maarten Altelaar, Jonathan W Yewdell, Pia Kvistborg, William J Faller

引用次数: 0

Regulation of angiogenesis and cancer cell proliferation by human vault RNA1-2. 人穹窿rna - 1-2对血管生成和癌细胞增殖的调控作用。

IF 3.2

NAR cancer Pub Date : 2025-08-30 eCollection Date: 2025-09-01 DOI: 10.1093/narcan/zcaf028

Stefano Gallo, Anastasiia Suspitsyna, Daniel Sanchez-Taltavull, Rafael Sebastián Fort, Maria Ana Duhagon, Deborah Stroka, Norbert Polacek

{"title":"Regulation of angiogenesis and cancer cell proliferation by human vault RNA1-2.","authors":"Stefano Gallo, Anastasiia Suspitsyna, Daniel Sanchez-Taltavull, Rafael Sebastián Fort, Maria Ana Duhagon, Deborah Stroka, Norbert Polacek","doi":"10.1093/narcan/zcaf028","DOIUrl":"10.1093/narcan/zcaf028","url":null,"abstract":"Noncoding RNAs play pivotal roles in tumorigenesis and cancer progression. Recent evidence has identified vault RNAs (vtRNAs) as critical regulators of cellular homeostasis. The human genome encodes four vtRNA paralogs, which are differentially expressed in cancer tissues and contribute to tumor development. The best studied vtRNA1-1 is involved in regulating apoptosis resistance, autophagy, lysosomal biogenesis, and drug resistance. Here, we present the first comprehensive characterization of vtRNA1-2 using a knockout hepatocellular carcinoma (HCC) cell line. Loss of vtRNA1-2 impaired cancer cell viability and proliferation by modulating mitogen-activated protein kinase signaling. Additionally, vtRNA1-2-deficient cells exhibited reduced motility and a decreased invasive potential. Unlike vtRNA1-1, vtRNA1-2 did not influence autophagy or lysosomal activity. Instead, vtRNA1-2 is implicated in the regulation of angiogenesis, a key process in tumor progression. VTRNA1-2-promoter hypomethylation is correlated with chromatin accessibility in liver cancer samples and we uncovered an association between promoter methylation and key patient clinical conditions as registered in the TCGA metadata. These findings highlight a distinct oncogenic role for vtRNA1-2 in HCC and suggest that it may serve as a potential therapeutic target. Our study underscores the functional divergence among vtRNA paralogs, supporting the concept that each exerts unique biological effects rather than acting as redundant molecular entities.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 3","pages":"zcaf028"},"PeriodicalIF":3.2,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Anti-tumorigenic properties by trichothiodystrophy mutations in melanocytic cells. 黑素细胞中毛硫营养不良突变的抗肿瘤特性。

IF 3.2

NAR cancer Pub Date : 2025-08-30 eCollection Date: 2025-09-01 DOI: 10.1093/narcan/zcaf026

Rupesh Paudel, Lena F Sorger, Anita Hufnagel, Mira Pasemann, Tamsanqa Hove, André Marquardt, Susanne Kneitz, Andreas Schlosser, Caroline Kisker, Jochen Kuper, Svenja Meierjohann

{"title":"Anti-tumorigenic properties by trichothiodystrophy mutations in melanocytic cells.","authors":"Rupesh Paudel, Lena F Sorger, Anita Hufnagel, Mira Pasemann, Tamsanqa Hove, André Marquardt, Susanne Kneitz, Andreas Schlosser, Caroline Kisker, Jochen Kuper, Svenja Meierjohann","doi":"10.1093/narcan/zcaf026","DOIUrl":"10.1093/narcan/zcaf026","url":null,"abstract":"Germline mutations in the DNA repair helicase XPD can cause the diseases xeroderma pigmentosum (XP) and trichothiodystrophy (TTD). XP patients bear an increased risk of skin cancer including melanoma. This is not observed for TTD patients despite DNA repair defects. To examine whether TTD cells harbor features counteracting tumorigenesis, we developed a TTD melanoma cell model containing the XPD variant R722W. Intriguingly, TTD melanoma cells exhibited reduced proliferation and an increased signature of the melanocyte lineage factor MITF, along with a strong basal upregulation of REDD2, an inhibitor of the mTOR/S6K/4EBP1-dependent messenger RNA (mRNA) translation machinery. REDD2 levels were partially driven by MITF and contributed to reduced melanoma proliferation. In a TTD model for melanocytes-the progenitor cells of melanoma-the MITF gene signature was also increased, but here without affecting REDD2 expression. However, ribosomal protein synthesis was reduced particularly in R722W melanocytes after UV stress, indicating a compromised mRNA translation machinery. Impaired translation was also demonstrated for the TTD XPD variant A725P, but not for an XP variant. Concludingly, the impaired translation and reduced fitness observed in TTD melanocytes and melanoma cells, particularly after UV stress, offer a possible explanation why TTD patients do not develop melanomas.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 3","pages":"zcaf026"},"PeriodicalIF":3.2,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inherent single-cell heterogeneity of the transcriptional response to hypoxia in cancer cells. 癌细胞对缺氧转录反应的单细胞异质性。

IF 3.2

NAR cancer Pub Date : 2025-08-28 eCollection Date: 2025-09-01 DOI: 10.1093/narcan/zcaf021

Małgorzata Wilk, Thomas Knöpfel, Stana M Burger, Stellor Nlandu Khodo, Roland H Wenger

{"title":"Inherent single-cell heterogeneity of the transcriptional response to hypoxia in cancer cells.","authors":"Małgorzata Wilk, Thomas Knöpfel, Stana M Burger, Stellor Nlandu Khodo, Roland H Wenger","doi":"10.1093/narcan/zcaf021","DOIUrl":"10.1093/narcan/zcaf021","url":null,"abstract":"Hypoxia-inducible factor (HIF) is a master regulator of cancer cell adaptation to tumor hypoxia and is involved in cancer progression. Single-cell (sc) differences in the HIF response allow for tumor evolution and cause therapy resistance. These sc-differences are usually ascribed to tumor microenvironmental differences and/or clonal (epi)genetic variability. However, the sc-heterogeneity of the HIF response in otherwise identical cells cultured under defined in vitro conditions has not yet been addressed. Therefore, we analyzed the sc-response to hypoxia in nonclonal cell lines and multiple clonal derivatives, including HIF-1α or HIF-2α knockouts. While HIF-1α and HIF-1 target mRNA sc-heterogeneity was slightly higher than global transcription or specific housekeeping messenger RNAs (mRNAs), HIF-2α and especially HIF-2 target mRNA sc-heterogeneity was extraordinary, and remained in independent clones following HIFα knockouts. Unexpectedly, neither HIF-2α mRNA nor nuclear protein levels correlated with target mRNA levels. Unsupervised but not supervised HIF target gene dimensionality reduction revealed the initial sample composition after scRNA-seq, demonstrating that, owing to sc-heterogeneity, individual HIF target genes are not sufficient to unequivocally identify hypoxic cancer cells. In conclusion, the pronounced intrinsic sc-heterogeneity of the HIF response represents a hitherto unrecognized feature of cancer cells that impairs clinical HIF pathway-dependent cancer cell identification and targeting.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 3","pages":"zcaf021"},"PeriodicalIF":3.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

m6A modification in R-loop homeostasis: a potential target for cancer therapeutics. r -环内稳态中的m6A修饰：癌症治疗的潜在靶点

IF 3.2

NAR cancer Pub Date : 2025-08-11 eCollection Date: 2025-09-01 DOI: 10.1093/narcan/zcaf022

Minh-Anh Vu, Manuela Spagnuolo, Chun-Long Chen

{"title":"m6A modification in R-loop homeostasis: a potential target for cancer therapeutics.","authors":"Minh-Anh Vu, Manuela Spagnuolo, Chun-Long Chen","doi":"10.1093/narcan/zcaf022","DOIUrl":"10.1093/narcan/zcaf022","url":null,"abstract":"R-loops or DNA-RNA hybrids are prominent nucleic acid structures that commonly arise during transcription. These structures play important biological functions, such as regulating gene expression and DNA repair. However, when unresolved by nucleic acid processing factors, pathological R-loops can be harmful and lead to genome instability. N 6-Methyladenosine (m6A), the most prevalent modification in messenger RNA, has been recently identified to be crucial for regulating R-loop balance and maintaining genome stability. Strikingly, m6A-modified R-loop formation can have opposing consequences, either stabilization or resolution, depending on the biological context. In this review, we discuss the current knowledge of the regulatory roles of m6A on R-loops across various processes, including gene transcription, DNA repair, and centromere and telomere stability. Additionally, we explore other m6A-mediated processes, such as nascent transcription and chromatin landscape, that potentially affect R-loop dynamics. Finally, we discuss the current limitations and future directions of studying the m6A-R-loop axis, as well as the opportunities to target this pathway as a potential therapeutic strategy.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 3","pages":"zcaf022"},"PeriodicalIF":3.2,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144850227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Automated machine learning profiling with MAP-HR for quantifying homologous recombination foci in patient samples. 自动机器学习分析与MAP-HR定量同源重组病灶的患者样本。

IF 3.2

NAR cancer Pub Date : 2025-08-11 eCollection Date: 2025-09-01 DOI: 10.1093/narcan/zcaf025

Tugba Y Ozmen, Matthew J Rames, Gabriel M Zangirolani, Furkan Ozmen, Kangjin Jeong, Connor Frankston, Gordon B Mills

{"title":"Automated machine learning profiling with MAP-HR for quantifying homologous recombination foci in patient samples.","authors":"Tugba Y Ozmen, Matthew J Rames, Gabriel M Zangirolani, Furkan Ozmen, Kangjin Jeong, Connor Frankston, Gordon B Mills","doi":"10.1093/narcan/zcaf025","DOIUrl":"10.1093/narcan/zcaf025","url":null,"abstract":"Accurate visualization and quantification of homologous recombination (HR)-associated foci in readily available patient samples are critical for identifying patients with HR deficiency (HRD) when they present for care to guide polyADP ribose polymerase (PARP) inhibitors (PARPi) or platinum-based therapies. Immunofluorescence (IF) assays have the potential to accurately visualize DNA repair processes as punctate foci within the nucleus. To ensure precise HRD assessment, we developed MAP-HR, (Machine-learning Assisted Profiling of Homologous Recombination), a scalable machine-learning (ML) analysis platform to enable effective patient triage and therapeutic decision-making. This workflow integrates high-resolution four-channel IF imaging and automated analysis of Geminin (cell cycle states), RAD51 foci (HR repair), γH2AX foci (double strand breaks) and DAPI (nuclear localization) in both cultured cell lines and in a single formalin-fixed, paraffin-embedded (FFPE) patient samples. Using a spinning disk confocal microscope, we optimized imaging parameters to improve resolution and signal-to-noise ratio. Our MAP-HR pipeline uses nested nuclei and segmentation of foci to analyze the HR status of each cell, unlike competing bulk or single-foci marker assays, allowing evaluation of HR functional heterogeneity across and within patient biopsies. This approach facilitates robust comparisons of HR and foci-based processes across diverse cell populations and patient tissues, enabling scalable, translational research.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 3","pages":"zcaf025"},"PeriodicalIF":3.2,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144850226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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