NAR cancer最新文献_第3页

The IGF2BP1 oncogene is a druggable m⁶A-dependent enhancer of YAP1-driven gene expression in ovarian cancer. IGF2BP1癌基因是卵巢癌中yap1驱动基因表达的可药物m6a依赖性增强子。

IF 3.4

NAR cancer Pub Date : 2025-02-24 eCollection Date: 2025-03-01 DOI: 10.1093/narcan/zcaf006

Annekatrin Schott, Theresa Simon, Simon Müller, Alexander Rausch, Bianca Busch, Markus Glaß, Danny Misiak, Mohammad Dipto, Hend Elrewany, Lara Meret Peters, Sunita Tripathee, Ehab Ghazy, Florian Müller, Robin Benedikt Rolnik, Marcell Lederer, Ali Hmedat, Martina Vetter, Markus Wallwiener, Wolfgang Sippl, Stefan Hüttelmaier, Nadine Bley

{"title":"The IGF2BP1 oncogene is a druggable m6A-dependent enhancer of YAP1-driven gene expression in ovarian cancer.","authors":"Annekatrin Schott, Theresa Simon, Simon Müller, Alexander Rausch, Bianca Busch, Markus Glaß, Danny Misiak, Mohammad Dipto, Hend Elrewany, Lara Meret Peters, Sunita Tripathee, Ehab Ghazy, Florian Müller, Robin Benedikt Rolnik, Marcell Lederer, Ali Hmedat, Martina Vetter, Markus Wallwiener, Wolfgang Sippl, Stefan Hüttelmaier, Nadine Bley","doi":"10.1093/narcan/zcaf006","DOIUrl":"10.1093/narcan/zcaf006","url":null,"abstract":"The Hippo/YAP1 signaling pathway regulates normal development by controlling contact inhibition of growth. In cancer, YAP1 activation is often dysregulated, leading to excessive tumor growth and metastasis. SRC kinase can cross talk to Hippo signaling by disrupting adherens junctions, repressing the Hippo cascade, or activating YAP1 to promote proliferation. Here, we demonstrate that the IGF2 messenger RNA-binding protein 1 (IGF2BP1) impedes the repression of YAP1 by Hippo signaling in carcinomas. IGF2BP1 stabilizes the YAP1 messenger RNA (mRNA) and enhances YAP1 protein synthesis through an m6A-dependent interaction with the 3' untranslated region of the YAP1 mRNA, thereby increasing YAP1/TAZ-driven transcription to bypass contact inhibition of tumor cell growth. Inhibiting IGF2BP1-mRNA binding using BTYNB reduces YAP1 levels and transcriptional activity, leading to significant growth inhibition in carcinoma cells and ovarian cancer organoids. In contrast, SRC inhibition with Saracatinib fails to inhibit YAP1/TAZ-driven transcription and cell growth in general. This is particularly significant in de-differentiated, rather mesenchymal carcinoma-derived cells, which exhibit high IGF2BP1 and YAP1 expression, rendering them less reliant on SRC-directed growth stimulation. In such invasive carcinoma models, the combined inhibition of SRC, IGF2BP1, and YAP1/TAZ proved superior over monotherapies. These findings highlight the therapeutic potential of targeting IGF2BP1, a key regulator of oncogenic transcription networks.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf006"},"PeriodicalIF":3.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506698","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

In vivo selection of anti-glioblastoma DNA aptamers in an orthotopic patient-derived xenograft model. 在原位患者来源的异种移植模型中抗胶质母细胞瘤DNA适体的体内选择。

IF 3.4

NAR cancer Pub Date : 2025-02-18 eCollection Date: 2025-03-01 DOI: 10.1093/narcan/zcaf005

Caroline D Doherty, Brandon A Wilbanks, Sonia Jain, Keenan S Pearson, Katie K Bakken, Danielle M Burgenske, Nay Won Lett, Jann N Sarkaria, Louis J Maher

{"title":"In vivo selection of anti-glioblastoma DNA aptamers in an orthotopic patient-derived xenograft model.","authors":"Caroline D Doherty, Brandon A Wilbanks, Sonia Jain, Keenan S Pearson, Katie K Bakken, Danielle M Burgenske, Nay Won Lett, Jann N Sarkaria, Louis J Maher","doi":"10.1093/narcan/zcaf005","DOIUrl":"10.1093/narcan/zcaf005","url":null,"abstract":"Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor of adults. Current therapeutic options yield dismal prognoses that have remained essentially unchanged over nearly two decades. Diffuse growth patterns, high intratumoral heterogeneity, and variable blood-brain barrier integrity limit treatment efficacy, creating challenges that rational small molecule design has not overcome. Antibody-drug conjugates have shown some promise, leading us to hypothesize that smaller folded DNA aptamers, developed in vivo via principles of natural selection, might eventually have advantages for drug delivery. Here, we document the first in vivo DNA aptamer selection involving an orthotopic patient-derived xenograft GBM mouse model to identify tumor-homing DNA aptamers. We demonstrate the preferential accumulation of these aptamers in the tumor relative to other tissues 4 h after intraperitoneal injection. The aptamers can be detected by quantitative polymerase chain reaction, fluorescent tumor staining, and stain GBM tumor section from untreated mice and the GBM tumor cells in culture. Two of three candidates are selective for the target cell line in vitro and do not bind other human tumor cells. In vivo selection of tumor-specific DNA aptamers demonstrates a novel approach for diagnostics or toxin delivery that might allow for the development of individualized therapies.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf005"},"PeriodicalIF":3.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451322","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

Therapy enhancing chromosome instability may be advantageous for IDH1 ^R132H/WT gliomas. 增强染色体不稳定性的治疗可能对IDH1 R132H/WT胶质瘤有利。

IF 3.4

NAR cancer Pub Date : 2025-02-13 eCollection Date: 2025-03-01 DOI: 10.1093/narcan/zcaf003

Nikolay V Goncharov, Ivan N Baklanov, Valeriia S Gulaia, Anastasiia P Shuliak, Daria V Lanskikh, Valeriia M Zhmenia, Mikhail E Shmelev, Nikita A Shved, Jing Wu, Mikhail Liskovykh, Vladimir Larionov, Natalay Kouprina, Vadim V Kumeiko

{"title":"Therapy enhancing chromosome instability may be advantageous for IDH1 R132H/WT gliomas.","authors":"Nikolay V Goncharov, Ivan N Baklanov, Valeriia S Gulaia, Anastasiia P Shuliak, Daria V Lanskikh, Valeriia M Zhmenia, Mikhail E Shmelev, Nikita A Shved, Jing Wu, Mikhail Liskovykh, Vladimir Larionov, Natalay Kouprina, Vadim V Kumeiko","doi":"10.1093/narcan/zcaf003","DOIUrl":"10.1093/narcan/zcaf003","url":null,"abstract":"Recently revised brain tumor classification suggested a glioma treatment strategy that takes into consideration molecular variants in IDH1 and TP53 marker genes. While pathogenic variants of IDH1 and TP53 can be accompanied by chromosomal instability (CIN), the impact of IDH1 and TP53 mutations on genome stability remains unstudied. Elevated CIN might provide therapeutic targets, based on synergistic effects of chemotherapy with CIN-inducing drugs. Using an assay based on human artificial chromosomes, we investigated the impact of common glioma missense mutations in IDH1 and TP53 on chromosome transmission and demonstrated that IDH1R132H and TP53R248Q variants elevate CIN. We next found enhanced CIN levels and the sensitivity of IDH1 R132H/WT and TP53 R248Q/R248Q genotypes, introduced into U87 MG glioma cells by CRISPR/Cas9, to different drugs, including conventional temozolomide. It was found that U87 MG cells carrying IDH1 R132H/WT exhibit dramatic sensitivity to paclitaxel, which was independently confirmed on cell cultures derived from patients with naturally occurring IDH1 R132H/WT. Overall, our results suggest that the development of CIN-enhancing therapy for glioma tumors with the IDH1 R132H/WT genotype could be advantageous for adjuvant treatment.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf003"},"PeriodicalIF":3.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416647","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

Effects of hydrazone-based G-quadruplex ligands on FANCJ/BRIP1-depleted cancer cells and a Caenorhabditis elegans dog-1^-/- strain. 基于腙的g-四联体配体对FANCJ/ brip1缺失癌细胞和秀丽隐杆线虫狗-1-/-菌株的影响

IF 3.4

NAR cancer Pub Date : 2025-02-08 eCollection Date: 2025-03-01 DOI: 10.1093/narcan/zcaf004

Marcello Germoglio, Federica D'Aria, Giuseppe Cortone, Antonello Prodomo, Mohammad Mahtab, Rita Morigi, Jussara Amato, Francesca M Pisani, Concetta Giancola

{"title":"Effects of hydrazone-based G-quadruplex ligands on FANCJ/BRIP1-depleted cancer cells and a Caenorhabditis elegans dog-1-/- strain.","authors":"Marcello Germoglio, Federica D'Aria, Giuseppe Cortone, Antonello Prodomo, Mohammad Mahtab, Rita Morigi, Jussara Amato, Francesca M Pisani, Concetta Giancola","doi":"10.1093/narcan/zcaf004","DOIUrl":"10.1093/narcan/zcaf004","url":null,"abstract":"G-quadruplex (G4) DNAs are alternative nucleic acid structures, proposed to play important roles in regulating DNA replication, gene transcription, and translation. Several specialized DNA helicases are involved in cellular G4 metabolism, in some cases with redundant functions. Among them, human FANCJ/BRIP1, which has orthologs in all metazoans, is one of the most powerful G4 resolvases, believed to act mainly at DNA replication forks. Here, we tested the effects of a set of hydrazone-derivative G4 ligands in a FANCJ-knocked-out HeLa cell line and in a Caenorhabditis elegans strain, where DOG-1, a FANCJ ortholog, was disrupted, as a whole organism model system. Our results revealed that loss of FANCJ specifically sensitized cancer cells to FIM-15, a mono-guanylhydrazone derivative bearing the diimidazopyrimidine core, among the tested hydrazone-based compounds and induced enhanced DNA damage in different chromosomal sites including telomeric ends. Moreover, dietary administration of FIM-15 to dog-1 -/- nematodes stabilized G4 structures in gonadal cell nuclei and resulted in compromised embryonic development in the first-generation post-treatment. Collectively, our findings unveil a specific vulnerability of FANCJ-knocked-out cancer cells (and DOG-1-lacking worms) to G4 stabilization by the FIM-15 compound. This study provides an important proof-of-principle for use of G4 ligands in synthetic lethality-based therapeutic approaches targeting FANCJ-defective cancer cells.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf004"},"PeriodicalIF":3.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143384559","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

Histone H3E50K remodels chromatin to confer oncogenic activity and support an EMT phenotype. 组蛋白H3E50K重塑染色质，赋予致癌活性并支持EMT表型。

IF 3.2

NAR cancer Pub Date : 2025-02-03 eCollection Date: 2025-03-01 DOI: 10.1093/narcan/zcaf002

Kirti Sad, Dorelle V Fawwal, Celina Y Jones, Emily J Hill, Katie T Skinner, Miranda L Adams, Severin Lustenberger, Richard S Lee, Sandhya V Lohano, Satvik R Elayavalli, Jonathan Farhi, Christina C Mehta, Laramie D Lemon, Milo B Fasken, Andrew L Hong, Steven A Sloan, Anita H Corbett, Jennifer M Spangle

{"title":"Histone H3E50K remodels chromatin to confer oncogenic activity and support an EMT phenotype.","authors":"Kirti Sad, Dorelle V Fawwal, Celina Y Jones, Emily J Hill, Katie T Skinner, Miranda L Adams, Severin Lustenberger, Richard S Lee, Sandhya V Lohano, Satvik R Elayavalli, Jonathan Farhi, Christina C Mehta, Laramie D Lemon, Milo B Fasken, Andrew L Hong, Steven A Sloan, Anita H Corbett, Jennifer M Spangle","doi":"10.1093/narcan/zcaf002","DOIUrl":"10.1093/narcan/zcaf002","url":null,"abstract":"Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype. Expression of H3E50K is sufficient to transform human cells as evidenced by an increase in cell migration and invasion, and an increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K selectively increases chromatin accessibility and perturbs proximal H3 post-translational modifications including H3K27me3; together these changes to chromatin dynamics dysregulate gene expression to support the epithelial-to-mesenchymal transition. Functional studies using Saccharomyces cerevisiae reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional H3 mutations have the potential to support oncogenic activity and function through distinct mechanisms that dysregulate gene expression.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf002"},"PeriodicalIF":3.2,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124145","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

Specific modulation of 28S_Um2402 rRNA 2'-O-ribose methylation as a novel epitranscriptomic marker of ZEB1-induced epithelial-mesenchymal transition in different mammary cell contexts. 28S_Um2402 rRNA 2'- o -核糖甲基化的特异性调节作为zeb1诱导的不同乳腺细胞上皮-间质转化的新表转录组学标记。

IF 3.4

NAR cancer Pub Date : 2025-01-28 eCollection Date: 2025-03-01 DOI: 10.1093/narcan/zcaf001

Chloé Morin, Hermes Paraqindes, Flora Nguyen Van Long, Caroline Isaac, Emilie Thomas, Dennis Pedri, Carlos Ariel Pulido-Vicuna, Anne-Pierre Morel, Virginie Marchand, Yuri Motorin, Marjorie Carrere, Jessie Auclair, Valéry Attignon, Roxane M Pommier, Emmanuelle Ruiz, Fleur Bourdelais, Frédéric Catez, Sébastien Durand, Anthony Ferrari, Alain Viari, Jean-Christophe Marine, Alain Puisieux, Jean-Jacques Diaz, Caroline Moyret-Lalle, Virginie Marcel

{"title":"Specific modulation of 28S_Um2402 rRNA 2'-O-ribose methylation as a novel epitranscriptomic marker of ZEB1-induced epithelial-mesenchymal transition in different mammary cell contexts.","authors":"Chloé Morin, Hermes Paraqindes, Flora Nguyen Van Long, Caroline Isaac, Emilie Thomas, Dennis Pedri, Carlos Ariel Pulido-Vicuna, Anne-Pierre Morel, Virginie Marchand, Yuri Motorin, Marjorie Carrere, Jessie Auclair, Valéry Attignon, Roxane M Pommier, Emmanuelle Ruiz, Fleur Bourdelais, Frédéric Catez, Sébastien Durand, Anthony Ferrari, Alain Viari, Jean-Christophe Marine, Alain Puisieux, Jean-Jacques Diaz, Caroline Moyret-Lalle, Virginie Marcel","doi":"10.1093/narcan/zcaf001","DOIUrl":"10.1093/narcan/zcaf001","url":null,"abstract":"The epithelial-mesenchymal transition (EMT) is a dynamic transdifferentiation of epithelial cells into mesenchymal cells. EMT programs exhibit great diversity, based primarily on the distinct impact of molecular activities of the EMT transcription factors. Using a panel of cancer cell lines and a series of 71 triple-negative primary breast tumors, we report that the EMT transcription factor ZEB1 modulates site-specific chemical modifications of ribosomal RNA (rRNA). Overexpression of ZEB1 and ZEB2, but not TWIST1, decreased the level of 2'-O-ribose methylation (2'Ome) of 28S rRNA at position Um2402. ZEB1 overexpression specifically reduced the expression of the corresponding C/D box small nucleolar RNAs (snoRNAs) SNORD143/144, which guide the rRNA 2'Ome complex at the 28S_Um2402 site. During ZEB1-induced EMT induction/reversion, the levels of both 2'Ome at 28S_Um2402 and SNORD143/144 were dynamically comodulated. Taken together, these data demonstrate that 2'Ome rRNA epitranscriptomics is a novel marker of ZEB1-induced EMT.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf001"},"PeriodicalIF":3.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061822","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 Atlas of Protein-Protein Interactions in Cancer (APPIC)-a webtool to visualize and analyze cancer subtypes. 癌症中蛋白质-蛋白质相互作用图谱(APPIC)-一个可视化和分析癌症亚型的网络工具。

IF 3.4

NAR cancer Pub Date : 2025-01-15 eCollection Date: 2025-03-01 DOI: 10.1093/narcan/zcae047

Benjamin Ahn, Charissa Chou, Caden Chou, Jennifer Chen, Amelia Zug, Yigit Baykara, Jessica Claus, Sean M Hacking, Alper Uzun, Ece D Gamsiz Uzun

{"title":"The Atlas of Protein-Protein Interactions in Cancer (APPIC)-a webtool to visualize and analyze cancer subtypes.","authors":"Benjamin Ahn, Charissa Chou, Caden Chou, Jennifer Chen, Amelia Zug, Yigit Baykara, Jessica Claus, Sean M Hacking, Alper Uzun, Ece D Gamsiz Uzun","doi":"10.1093/narcan/zcae047","DOIUrl":"10.1093/narcan/zcae047","url":null,"abstract":"Cancer is a complex disease with heterogeneous mutational and gene expression patterns. Subgroups of patients who share a phenotype might share a specific genetic architecture including protein-protein interactions (PPIs). We developed the Atlas of Protein-Protein Interactions in Cancer (APPIC), an interactive webtool that provides PPI subnetworks of 10 cancer types and their subtypes shared by cohorts of patients. To achieve this, we analyzed publicly available RNA sequencing data from patients and identified PPIs specific to 26 distinct cancer subtypes. APPIC compiles biological and clinical information from various databases, including the Human Protein Atlas, Hugo Gene Nomenclature Committee, g:Profiler, cBioPortal and Clue.io. The user-friendly interface allows for both 2D and 3D PPI network visualizations, enhancing the usability and interpretability of complex data. For advanced users seeking greater customization, APPIC conveniently provides all output files for further analysis and visualization on other platforms or tools. By offering comprehensive insights into PPIs and their role in cancer, APPIC aims to support the discovery of tumor subtype-specific novel targeted therapeutics and drug repurposing. APPIC is freely available at https://appic.brown.edu.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcae047"},"PeriodicalIF":3.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143019152","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

Spatial transcriptomics in breast cancer reveals tumour microenvironment-driven drug responses and clonal therapeutic heterogeneity. 乳腺癌的空间转录组学揭示了肿瘤微环境驱动的药物反应和克隆治疗异质性。

IF 3.4

NAR cancer Pub Date : 2024-12-18 eCollection Date: 2024-12-01 DOI: 10.1093/narcan/zcae046

María José Jiménez-Santos, Santiago García-Martín, Marcos Rubio-Fernández, Gonzalo Gómez-López, Fátima Al-Shahrour

{"title":"Spatial transcriptomics in breast cancer reveals tumour microenvironment-driven drug responses and clonal therapeutic heterogeneity.","authors":"María José Jiménez-Santos, Santiago García-Martín, Marcos Rubio-Fernández, Gonzalo Gómez-López, Fátima Al-Shahrour","doi":"10.1093/narcan/zcae046","DOIUrl":"10.1093/narcan/zcae046","url":null,"abstract":"Breast cancer patients are categorized into three subtypes with distinct treatment approaches. Precision oncology has increased patient outcomes by targeting the specific molecular alterations of tumours, yet challenges remain. Treatment failure persists due to the coexistence of several malignant subpopulations with different drug sensitivities within the same tumour, a phenomenon known as intratumour heterogeneity (ITH). This heterogeneity has been extensively studied from a tumour-centric view, but recent insights underscore the role of the tumour microenvironment in treatment response. Our research utilizes spatial transcriptomics data from breast cancer patients to predict drug sensitivity. We observe diverse response patterns across tumour, interphase and microenvironment regions, unveiling a sensitivity and functional gradient from the tumour core to the periphery. Moreover, we find tumour therapeutic clusters with different drug responses associated with distinct biological functions driven by unique ligand-receptor interactions. Importantly, we identify genetically identical subclones with different responses depending on their location within the tumour ducts. This research underscores the significance of considering the distance from the tumour core and microenvironment composition when identifying suitable treatments to target ITH. Our findings provide critical insights into optimizing therapeutic strategies, highlighting the necessity of a comprehensive understanding of tumour biology for effective cancer treatment.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 4","pages":"zcae046"},"PeriodicalIF":3.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866848","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

RAD51 recruitment but not replication fork stability associates with PARP inhibitor response in ovarian cancer patient-derived xenograft models. 在卵巢癌患者来源的异种移植模型中，RAD51募集而非复制叉稳定性与PARP抑制剂反应相关。

IF 3.4

NAR cancer Pub Date : 2024-11-28 eCollection Date: 2024-12-01 DOI: 10.1093/narcan/zcae044

Francien Talens, Vivian Oliviera Nunes Teixeira, Yannick P Kok, Mengting Chen, Efraim H Rosenberg, Rashmie Debipersad, Evelien W Duiker, Nathalie van den Tempel, Marketa Janatova, Petra Zemankova, Petra M Nederlof, G Bea A Wisman, Zdenek Kleibl, Steven de Jong, Marcel A T M van Vugt

{"title":"RAD51 recruitment but not replication fork stability associates with PARP inhibitor response in ovarian cancer patient-derived xenograft models.","authors":"Francien Talens, Vivian Oliviera Nunes Teixeira, Yannick P Kok, Mengting Chen, Efraim H Rosenberg, Rashmie Debipersad, Evelien W Duiker, Nathalie van den Tempel, Marketa Janatova, Petra Zemankova, Petra M Nederlof, G Bea A Wisman, Zdenek Kleibl, Steven de Jong, Marcel A T M van Vugt","doi":"10.1093/narcan/zcae044","DOIUrl":"10.1093/narcan/zcae044","url":null,"abstract":"Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently used to treat BRCA1/2 mutant cancers. Although PARPi sensitivity has been attributed to homologous recombination (HR) defects, other roles of HR factors have also been linked to response to PARPi, including replication fork protection. In this study, we investigated PARPi sensitivity in ovarian cancer patient-derived xenograft (PDX) models in relation to HR proficiency and replication fork protection. Analysis of BRCA1/2 status showed that in our cohort of 31 ovarian cancer PDX models 22.6% harbored a BRCA1/2 alteration (7/31), and 48.3% (15/31) were genomically unstable as measured by copy number alteration analysis. In vivo, PARPi olaparib response was measured in 15 selected PDX models. Functional assessment of HR using ex vivo irradiation-induced RAD51 foci formation identified all olaparib-sensitive PDX models, including four models without BRCA1/2 alterations. In contrast, replication fork protection or replication speed in ex vivo tumor tissue did not correlate with olaparib response. Targeted panel sequencing in olaparib-sensitive models lacking BRCA1/2 alterations revealed a MUS81 variant as a possible mechanism underlying PARPi sensitivity. Combined, we show that ex vivo RAD51 analysis effectively predicts in vivo olaparib response and revealed a subset of PARPi-sensitive, HR-deficient ovarian cancer PDX models, lacking a BRCA1/2 alteration.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 4","pages":"zcae044"},"PeriodicalIF":3.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11604054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752753","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

Expanded detection and impact of BAP1 alterations in cancer. 扩大癌症中 BAP1 改变的检测范围和影响。

IF 3.4

NAR cancer Pub Date : 2024-11-15 eCollection Date: 2024-12-01 DOI: 10.1093/narcan/zcae045

Ian R Sturgill, Jesse R Raab, Katherine A Hoadley

{"title":"Expanded detection and impact of BAP1 alterations in cancer.","authors":"Ian R Sturgill, Jesse R Raab, Katherine A Hoadley","doi":"10.1093/narcan/zcae045","DOIUrl":"10.1093/narcan/zcae045","url":null,"abstract":"Aberrant expression of the BAP1 (BRCA associated protein 1) tumor suppressor gene is a prominent risk factor for several tumor types and is important in tumor evolution and progression. Here we performed integrated multi-omics analyses using data from The Cancer Genome Atlas for 33 cancer types and over 10 000 individuals to identify alterations leading to BAP1 disruption. We combined existing variant calls and new calls derived from a de novo local realignment pipeline across multiple independent variant callers, increasing somatic variant detection by 41% from 182 to 257, including 11 indels ≥40 bp. The expanded detection of mutations highlights the power of new tools to uncover longer indels and impactful mutations. We developed an expression-based BAP1 activity score and identified a transcriptional profile associated with BAP1 disruption in cancer. BAP1 has been proposed to play a critical role in controlling tumor plasticity and normal cell fate. Leveraging human and mouse liver datasets, BAP1 loss in normal cells resulted in lower BAP1 activity scores and lower scores were associated with a less-differentiated phenotype in embryonic cells. Together, our expanded BAP1 mutant samples revealed a transcriptional signature in cancer cells, supporting BAP1's influences on cellular plasticity and cell identity maintenance.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 4","pages":"zcae045"},"PeriodicalIF":3.4,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649828","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}

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