NAR cancer最新文献_第3页

Rewiring of RNA methylation by the oncometabolite fumarate in renal cell carcinoma. 肾细胞癌中副代谢物富马酸盐对 RNA 甲基化的重排。

IF 3.4

NAR cancer Pub Date : 2024-02-07 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae004

Christina M Fitzsimmons, Mariana D Mandler, Judith C Lunger, Dalen Chan, Siddhardha S Maligireddy, Alexandra C Schmiechen, Supuni Thalalla Gamage, Courtney Link, Lisa M Jenkins, King Chan, Thorkell Andresson, Daniel R Crooks, Jordan L Meier, W Marston Linehan, Pedro J Batista

{"title":"Rewiring of RNA methylation by the oncometabolite fumarate in renal cell carcinoma.","authors":"Christina M Fitzsimmons, Mariana D Mandler, Judith C Lunger, Dalen Chan, Siddhardha S Maligireddy, Alexandra C Schmiechen, Supuni Thalalla Gamage, Courtney Link, Lisa M Jenkins, King Chan, Thorkell Andresson, Daniel R Crooks, Jordan L Meier, W Marston Linehan, Pedro J Batista","doi":"10.1093/narcan/zcae004","DOIUrl":"10.1093/narcan/zcae004","url":null,"abstract":"Metabolic reprogramming is a hallmark of cancer that facilitates changes in many adaptive biological processes. Mutations in the tricarboxylic acid cycle enzyme fumarate hydratase (FH) lead to fumarate accumulation and cause hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is a rare, inherited disease characterized by the development of non-cancerous smooth muscle tumors of the uterus and skin, and an increased risk of an aggressive form of kidney cancer. Fumarate has been shown to inhibit 2-oxoglutarate-dependent dioxygenases (2OGDDs) involved in the hydroxylation of HIF1α, as well as in DNA and histone demethylation. However, the link between fumarate accumulation and changes in RNA post-transcriptional modifications has not been defined. Here, we determine the consequences of fumarate accumulation on the activity of different members of the 2OGDD family targeting RNA modifications. By evaluating multiple RNA modifications in patient-derived HLRCC cell lines, we show that mutation of FH selectively affects the levels of N6-methyladenosine (m6A), while the levels of 5-formylcytosine (f5C) in mitochondrial tRNA are unaffected. This supports the hypothesis of a differential impact of fumarate accumulation on distinct RNA demethylases. The observation that metabolites modulate specific subsets of RNA-modifying enzymes offers new insights into the intersection between metabolism and the epitranscriptome.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10849186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139704355","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

A large-scale study of peptide features defining immunogenicity of cancer neo-epitopes. 对确定癌症新表位免疫原性的多肽特征进行大规模研究。

IF 3.4

NAR cancer Pub Date : 2024-01-29 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae002

Yat-Tsai Richie Wan, Zeynep Koşaloğlu-Yalçın, Bjoern Peters, Morten Nielsen

{"title":"A large-scale study of peptide features defining immunogenicity of cancer neo-epitopes.","authors":"Yat-Tsai Richie Wan, Zeynep Koşaloğlu-Yalçın, Bjoern Peters, Morten Nielsen","doi":"10.1093/narcan/zcae002","DOIUrl":"10.1093/narcan/zcae002","url":null,"abstract":"Accurate prediction of immunogenicity for neo-epitopes arising from a cancer associated mutation is a crucial step in many bioinformatics pipelines that predict outcome of checkpoint blockade treatments or that aim to design personalised cancer immunotherapies and vaccines. In this study, we performed a comprehensive analysis of peptide features relevant for prediction of immunogenicity using the Cancer Epitope Database and Analysis Resource (CEDAR), a curated database of cancer epitopes with experimentally validated immunogenicity annotations from peer-reviewed publications. The developed model, ICERFIRE (ICore-based Ensemble Random Forest for neo-epitope Immunogenicity pREdiction), extracts the predicted ICORE from the full neo-epitope as input, i.e. the nested peptide with the highest predicted major histocompatibility complex (MHC) binding potential combined with its predicted likelihood of antigen presentation (%Rank). Key additional features integrated into the model include assessment of the BLOSUM mutation score of the neo-epitope, and antigen expression levels of the wild-type counterpart which is often reflecting a neo-epitope's abundance. We demonstrate improved and robust performance of ICERFIRE over existing immunogenicity and epitope prediction models, both in cross-validation and on external validation datasets.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10823584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139577133","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 ORFIUS complex regulates ORC2 localization at replication origins. ORFIUS 复合物调节 ORC2 在复制起源的定位。

IF 3.4

NAR cancer Pub Date : 2024-01-29 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae003

Zelei Yang, Saie Mogre, Ruiyang He, Emma L Berdan, Shannan J Ho Sui, Sarah J Hill

{"title":"The ORFIUS complex regulates ORC2 localization at replication origins.","authors":"Zelei Yang, Saie Mogre, Ruiyang He, Emma L Berdan, Shannan J Ho Sui, Sarah J Hill","doi":"10.1093/narcan/zcae003","DOIUrl":"10.1093/narcan/zcae003","url":null,"abstract":"High-grade serous ovarian cancer (HGSC) is a lethal malignancy with elevated replication stress (RS) levels and defective RS and RS-associated DNA damage responses. Here we demonstrate that the bromodomain-containing protein BRD1 is a RS suppressing protein that forms a replication origin regulatory complex with the histone acetyltransferase HBO1, the BRCA1 tumor suppressor, and BARD1, ORigin FIring Under Stress (ORFIUS). BRD1 and HBO1 promote eventual origin firing by supporting localization of the origin licensing protein ORC2 at origins. In the absence of BRD1 and/or HBO1, both origin firing and nuclei with ORC2 foci are reduced. BRCA1 regulates BRD1, HBO1, and ORC2 localization at replication origins. In the absence of BRCA1, both origin firing and nuclei with BRD1, HBO1, and ORC2 foci are increased. In normal and non-HGSC ovarian cancer cells, the ORFIUS complex responds to ATR and CDC7 origin regulatory signaling and disengages from origins during RS. In BRCA1-mutant and sporadic HGSC cells, BRD1, HBO1, and ORC2 remain associated with replication origins, and unresponsive to RS, DNA damage, or origin regulatory kinase inhibition. ORFIUS complex dysregulation may promote HGSC cell survival by allowing for upregulated origin firing and cell cycle progression despite accumulating DNA damage, and may be a RS target.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10823580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139577136","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

Single-cell genomics analysis reveals complex genetic interactions in an in vivo model of acquired BRAF inhibitor resistance. 单细胞基因组学分析揭示了获得性 BRAF 抑制剂耐药性体内模型中复杂的基因相互作用。

NAR cancer Pub Date : 2024-01-11 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcad061

Jacob L Schillo, Charlotte R Feddersen, Rebekah M Peplinski, Lexy S Powell, Afshin Varzavand, Christopher S Stipp, Jesse D Riordan, Adam J Dupuy

{"title":"Single-cell genomics analysis reveals complex genetic interactions in an in vivo model of acquired BRAF inhibitor resistance.","authors":"Jacob L Schillo, Charlotte R Feddersen, Rebekah M Peplinski, Lexy S Powell, Afshin Varzavand, Christopher S Stipp, Jesse D Riordan, Adam J Dupuy","doi":"10.1093/narcan/zcad061","DOIUrl":"10.1093/narcan/zcad061","url":null,"abstract":"The evolution of therapeutic resistance is a major obstacle to the success of targeted oncology drugs. While both inter- and intratumoral heterogeneity limit our ability to detect resistant subpopulations that pre-exist or emerge during treatment, our ability to analyze tumors with single-cell resolution is limited. Here, we utilized a cell-based transposon mutagenesis method to identify mechanisms of BRAF inhibitor resistance in a model of cutaneous melanoma. This screen identified overexpression of NEDD4L and VGLL3 as significant drivers of BRAF inhibitor resistance in vivo. In addition, we describe a novel single-cell genomics profiling method to genotype thousands of individual cells within tumors driven by transposon mutagenesis. This approach revealed a surprising genetic diversity among xenograft tumors and identified recurrent co-occurring mutations that emerge within distinct tumor subclones. Taken together, these observations reveal an unappreciated genetic complexity that drives BRAF inhibitor resistance.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10782916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139428199","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

Codelivery of TGFβ and Cox2 siRNA inhibits HCC by promoting T-cell penetration into the tumor and improves response to Immune Checkpoint Inhibitors. TGFβ和Cox2 siRNA联合递送可通过促进T细胞穿透肿瘤抑制HCC，并改善对免疫检查点抑制剂的反应。

NAR cancer Pub Date : 2024-01-09 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcad059

Wookhyun Kim, Zhou Ye, Vera Simonenko, Aashirwad Shahi, Asra Malikzay, Steven Z Long, John J Xu, Alan Lu, Jau-Hau Horng, Chang-Ru Wu, Pei-Jer Chen, Patrick Y Lu, David M Evans

{"title":"Codelivery of TGFβ and Cox2 siRNA inhibits HCC by promoting T-cell penetration into the tumor and improves response to Immune Checkpoint Inhibitors.","authors":"Wookhyun Kim, Zhou Ye, Vera Simonenko, Aashirwad Shahi, Asra Malikzay, Steven Z Long, John J Xu, Alan Lu, Jau-Hau Horng, Chang-Ru Wu, Pei-Jer Chen, Patrick Y Lu, David M Evans","doi":"10.1093/narcan/zcad059","DOIUrl":"10.1093/narcan/zcad059","url":null,"abstract":"Upregulation of TGFβ and Cox2 in the tumor microenvironment results in blockade of T-cell penetration into the tumor. Without access to tumor antigens, the T-cell response will not benefit from administration of the immune checkpoint antibodies. We created an intravenous polypeptide nanoparticle that can deliver two siRNAs (silencing TGFβ and Cox2). Systemic administration in mice, bearing a syngeneic orthotopic hepatocellular carcinoma (HCC), delivers the siRNAs to various cells in the liver, and significantly reduces the tumor. At 2 mg/kg (BIW) the nanoparticle demonstrated a single agent action and induced tumor growth inhibition to undetectable levels after five doses. Reducing the siRNAs to 1mg/kg BIW demonstrated greater inhibition in the presence of PD-L1 mAbs. After only three doses BIW, we could still recover a smaller tumor and, in tumor sections, showed an increase in penetration of CD4+ and CD8+ T-cells deeper into the remaining tumor that was not evident in animals treated with non-silencing siRNA. The combination of TGFβ and Cox2 siRNA co-administered in a polypeptide nanoparticle can act as a novel therapeutic alone against HCC and may augment the activity of the immune checkpoint antibodies. Silencing TGFβ and Cox2 converts an immune excluded (cold) tumor into a T-cell inflamed (hot) tumor.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10776204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139418788","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

An impaired ubiquitin-proteasome system increases APOBEC3A abundance. 泛素-蛋白酶体系统受损会增加 APOBEC3A 的丰度。

NAR cancer Pub Date : 2023-12-19 eCollection Date: 2023-12-01 DOI: 10.1093/narcan/zcad058

Margo Coxon, Madeline A Dennis, Alexandra Dananberg, Christopher D Collins, Hannah E Wilson, Jordyn Meekma, Marina I Savenkova, Daniel Ng, Chelsea A Osbron, Tony M Mertz, Alan G Goodman, Sascha H Duttke, John Maciejowski, Steven A Roberts

{"title":"An impaired ubiquitin-proteasome system increases APOBEC3A abundance.","authors":"Margo Coxon, Madeline A Dennis, Alexandra Dananberg, Christopher D Collins, Hannah E Wilson, Jordyn Meekma, Marina I Savenkova, Daniel Ng, Chelsea A Osbron, Tony M Mertz, Alan G Goodman, Sascha H Duttke, John Maciejowski, Steven A Roberts","doi":"10.1093/narcan/zcad058","DOIUrl":"10.1093/narcan/zcad058","url":null,"abstract":"Apolipoprotein B messenger RNA (mRNA) editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases cause genetic instability during cancer development. Elevated APOBEC3A (A3A) levels result in APOBEC signature mutations; however, mechanisms regulating A3A abundance in breast cancer are unknown. Here, we show that dysregulating the ubiquitin-proteasome system with proteasome inhibitors, including Food and Drug Administration-approved anticancer drugs, increased A3A abundance in breast cancer and multiple myeloma cell lines. Unexpectedly, elevated A3A occurs via an ∼100-fold increase in A3A mRNA levels, indicating that proteasome inhibition triggers a transcriptional response as opposed to or in addition to blocking A3A degradation. This transcriptional regulation is mediated in part through FBXO22, a protein that functions in SKP1-cullin-F-box ubiquitin ligase complexes and becomes dysregulated during carcinogenesis. Proteasome inhibitors increased cellular cytidine deaminase activity, decreased cellular proliferation and increased genomic DNA damage in an A3A-dependent manner. Our findings suggest that proteasome dysfunction, either acquired during cancer development or induced therapeutically, could increase A3A-induced genetic heterogeneity and thereby influence therapeutic responses in patients.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10753533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139059395","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

Detection of oxaliplatin- and cisplatin-DNA lesions requires different global genome repair mechanisms that affect their clinical efficacy. 检测奥沙利铂和顺铂dna病变需要不同的全基因组修复机制，从而影响其临床疗效。

IF 3.4

NAR cancer Pub Date : 2023-12-05 eCollection Date: 2023-12-01 DOI: 10.1093/narcan/zcad057

Jana Slyskova, Alba Muniesa-Vargas, Israel Tojal da Silva, Rodrigo Drummond, Jiyeong Park, David Häckes, Isabella Poetsch, Cristina Ribeiro-Silva, Amandine Moretton, Petra Heffeter, Orlando D Schärer, Wim Vermeulen, Hannes Lans, Joanna I Loizou

{"title":"Detection of oxaliplatin- and cisplatin-DNA lesions requires different global genome repair mechanisms that affect their clinical efficacy.","authors":"Jana Slyskova, Alba Muniesa-Vargas, Israel Tojal da Silva, Rodrigo Drummond, Jiyeong Park, David Häckes, Isabella Poetsch, Cristina Ribeiro-Silva, Amandine Moretton, Petra Heffeter, Orlando D Schärer, Wim Vermeulen, Hannes Lans, Joanna I Loizou","doi":"10.1093/narcan/zcad057","DOIUrl":"10.1093/narcan/zcad057","url":null,"abstract":"The therapeutic efficacy of cisplatin and oxaliplatin depends on the balance between the DNA damage induction and the DNA damage response of tumor cells. Based on clinical evidence, oxaliplatin is administered to cisplatin-unresponsive cancers, but the underlying molecular causes for this tumor specificity are not clear. Hence, stratification of patients based on DNA repair profiling is not sufficiently utilized for treatment selection. Using a combination of genetic, transcriptomics and imaging approaches, we identified factors that promote global genome nucleotide excision repair (GG-NER) of DNA-platinum adducts induced by oxaliplatin, but not by cisplatin. We show that oxaliplatin-DNA lesions are a poor substrate for GG-NER initiating factor XPC and that DDB2 and HMGA2 are required for efficient binding of XPC to oxaliplatin lesions and subsequent GG-NER initiation. Loss of DDB2 and HMGA2 therefore leads to hypersensitivity to oxaliplatin but not to cisplatin. As a result, low DDB2 levels in different colon cancer cells are associated with GG-NER deficiency and oxaliplatin hypersensitivity. Finally, we show that colon cancer patients with low DDB2 levels have a better prognosis after oxaliplatin treatment than patients with high DDB2 expression. We therefore propose that DDB2 is a promising predictive marker of oxaliplatin treatment efficiency in colon cancer.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138500566","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

Gene essentiality in cancer is better predicted by mRNA abundance than by gene regulatory network-inferred activity. 基因在癌症中的重要性通过mRNA丰度比通过基因调控网络推断的活性更好地预测。

IF 3.4

NAR cancer Pub Date : 2023-11-28 eCollection Date: 2023-12-01 DOI: 10.1093/narcan/zcad056

Cosmin Tudose, Jonathan Bond, Colm J Ryan

{"title":"Gene essentiality in cancer is better predicted by mRNA abundance than by gene regulatory network-inferred activity.","authors":"Cosmin Tudose, Jonathan Bond, Colm J Ryan","doi":"10.1093/narcan/zcad056","DOIUrl":"10.1093/narcan/zcad056","url":null,"abstract":"Gene regulatory networks (GRNs) are often deregulated in tumor cells, resulting in altered transcriptional programs that facilitate tumor growth. These altered networks may make tumor cells vulnerable to the inhibition of specific regulatory proteins. Consequently, the reconstruction of GRNs in tumors is often proposed as a means to identify therapeutic targets. While there are examples of individual targets identified using GRNs, the extent to which GRNs can be used to predict sensitivity to targeted intervention in general remains unknown. Here we use the results of genome-wide CRISPR screens to systematically assess the ability of GRNs to predict sensitivity to gene inhibition in cancer cell lines. Using GRNs derived from multiple sources, including GRNs reconstructed from tumor transcriptomes and from curated databases, we infer regulatory gene activity in cancer cell lines from ten cancer types. We then ask, in each cancer type, if the inferred regulatory activity of each gene is predictive of sensitivity to CRISPR perturbation of that gene. We observe slight variation in the correlation between gene regulatory activity and gene sensitivity depending on the source of the GRN and the activity estimation method used. However, we find that there is consistently a stronger relationship between mRNA abundance and gene sensitivity than there is between regulatory gene activity and gene sensitivity. This is true both when gene sensitivity is treated as a binary and a quantitative property. Overall, our results suggest that gene sensitivity is better predicted by measured expression than by GRN-inferred activity.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10683780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138465247","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

Single-cell transcriptomics reveals long noncoding RNAs associated with tumor biology and the microenvironment in pancreatic cancer. 单细胞转录组学揭示了胰腺癌中与肿瘤生物学和微环境相关的长链非编码rna。

NAR cancer Pub Date : 2023-11-22 eCollection Date: 2023-12-01 DOI: 10.1093/narcan/zcad055

Ha X Dang, Debanjan Saha, Reyka Jayasinghe, Sidi Zhao, Emily Coonrod, Jacqueline Mudd, S Peter Goedegebuure, Ryan Fields, Li Ding, Christopher A Maher

{"title":"Single-cell transcriptomics reveals long noncoding RNAs associated with tumor biology and the microenvironment in pancreatic cancer.","authors":"Ha X Dang, Debanjan Saha, Reyka Jayasinghe, Sidi Zhao, Emily Coonrod, Jacqueline Mudd, S Peter Goedegebuure, Ryan Fields, Li Ding, Christopher A Maher","doi":"10.1093/narcan/zcad055","DOIUrl":"10.1093/narcan/zcad055","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is highly heterogeneous and lethal. Long noncoding RNAs (lncRNAs) are an important class of genes regulating tumorigenesis and progression. Prior bulk transcriptomic studies in PDAC have revealed the dysregulation of lncRNAs but lack single-cell resolution to distinguish lncRNAs in tumor-intrinsic biology and the tumor microenvironment (TME). We analyzed single-cell transcriptome data from 73 multiregion samples in 21 PDAC patients to evaluate lncRNAs associated with intratumoral heterogeneity and the TME in PDAC. We found 111 cell-specific lncRNAs that reflected tumor, immune and stromal cell contributions, associated with outcomes, and validated across orthogonal datasets. Single-cell analysis of tumor cells revealed lncRNAs associated with TP53 mutations and FOLFIRINOX treatment that were obscured in bulk tumor analysis. Lastly, tumor subcluster analysis revealed widespread intratumor heterogeneity and intratumoral lncRNAs associated with cancer hallmarks and tumor processes such as angiogenesis, epithelial-mesenchymal transition, metabolism and immune signaling. Intratumoral subclusters and lncRNAs were validated across six datasets and showed clinically relevant associations with patient outcomes. Our study provides the first comprehensive assessment of the lncRNA landscape in PDAC using single-cell transcriptomic data and can serve as a resource, PDACLncDB (accessible at https://www.maherlab.com/pdaclncdb-overview), to guide future functional studies.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138465249","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 epitranscriptome analysis reveals differentially methylated transcripts that drive early chemoresistance in bladder cancer. m6A表转录组分析揭示了膀胱癌早期化疗耐药的差异甲基化转录物。

NAR cancer Pub Date : 2023-11-16 eCollection Date: 2023-12-01 DOI: 10.1093/narcan/zcad054

Emmanuelle Hodara, Aubree Mades, Lisa Swartz, Maheen Iqbal, Tong Xu, Daniel Bsteh, Peggy J Farnham, Suhn K Rhie, Amir Goldkorn

{"title":"m6A epitranscriptome analysis reveals differentially methylated transcripts that drive early chemoresistance in bladder cancer.","authors":"Emmanuelle Hodara, Aubree Mades, Lisa Swartz, Maheen Iqbal, Tong Xu, Daniel Bsteh, Peggy J Farnham, Suhn K Rhie, Amir Goldkorn","doi":"10.1093/narcan/zcad054","DOIUrl":"10.1093/narcan/zcad054","url":null,"abstract":"N 6-Methyladenosine (m6A) RNA modifications dynamically regulate messenger RNA processing, differentiation and cell fate. Given these functions, we hypothesized that m6A modifications play a role in the transition to chemoresistance. To test this, we took an agnostic discovery approach anchored directly to chemoresistance rather than to any particular m6A effector protein. Specifically, we used methyl-RNA immunoprecipitation followed by sequencing (MeRIP-seq) in parallel with RNA sequencing to identify gene transcripts that were both differentially methylated and differentially expressed between cisplatin-sensitive and cisplatin-resistant bladder cancer (BC) cells. We filtered and prioritized these genes using clinical and functional database tools, and then validated several of the top candidates via targeted quantitative polymerase chain reaction (qPCR) and MeRIP-PCR. In cisplatin-resistant cells, SLC7A11 transcripts had decreased methylation associated with decreased m6A reader YTHDF3 binding, prolonged RNA stability, and increased RNA and protein levels, leading to reduced ferroptosis and increased survival. Consistent with this, cisplatin-sensitive BC cell lines and patient-derived organoids exposed to cisplatin for as little as 48 h exhibited similar mechanisms of SLC7A11 upregulation and chemoresistance, trends that were also reflected in public cancer survival databases. Collectively, these findings highlight epitranscriptomic plasticity as a mechanism of rapid chemoresistance and a potential therapeutic target.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138465248","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