NAR cancer最新文献_第2页

TDP2 is a regulator of estrogen-responsive oncogene expression TDP2 是雌激素反应性癌基因表达的调节器

NAR cancer Pub Date : 2024-04-08 DOI: 10.1093/narcan/zcae016

N. Manguso, Minhyung Kim, Neeraj Joshi, Md Rasel Al Mahmud, Juan Aldaco, Ryusuke Suzuki, Felipe Cortés-Ledesma, Xiaojiang Cui, Shintaro Yamada, Shunichi Takeda, Armando Giuliano, Sungyong You, Hisashi Tanaka

{"title":"TDP2 is a regulator of estrogen-responsive oncogene expression","authors":"N. Manguso, Minhyung Kim, Neeraj Joshi, Md Rasel Al Mahmud, Juan Aldaco, Ryusuke Suzuki, Felipe Cortés-Ledesma, Xiaojiang Cui, Shintaro Yamada, Shunichi Takeda, Armando Giuliano, Sungyong You, Hisashi Tanaka","doi":"10.1093/narcan/zcae016","DOIUrl":"https://doi.org/10.1093/narcan/zcae016","url":null,"abstract":"Abstract With its ligand estrogen, the estrogen receptor (ER) initiates a global transcriptional program, promoting cell growth. This process involves topoisomerase 2 (TOP2), a key protein in resolving topological issues during transcription by cleaving a DNA duplex, passing another duplex through the break, and repairing the break. Recent studies revealed the involvement of various DNA repair proteins in the repair of TOP2-induced breaks, suggesting potential alternative repair pathways in cases where TOP2 is halted after cleavage. However, the contribution of these proteins in ER-induced transcriptional regulation remains unclear. We investigated the role of tyrosyl-DNA phosphodiesterase 2 (TDP2), an enzyme for the removal of halted TOP2 from the DNA ends, in the estrogen-induced transcriptome using both targeted and global transcription analyses. MYC activation by estrogen, a TOP2-dependent and transient event, became prolonged in the absence of TDP2 in both TDP2-deficient cells and mice. Bulk and single-cell RNA-seq analyses defined MYC and CCND1 as oncogenes whose estrogen response is tightly regulated by TDP2. These results suggest that TDP2 may inherently participate in the repair of estrogen-induced breaks at specific genomic loci, exerting precise control over oncogenic gene expression.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140730859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

XPA tumor variant leads to defects in NER that sensitize cells to cisplatin. XPA 肿瘤变体导致 NER 缺陷，使细胞对顺铂敏感。

IF 3.4

NAR cancer Pub Date : 2024-03-18 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae013

Alexandra M Blee, Kaitlyn S Gallagher, Hyun-Suk Kim, Mihyun Kim, Suhas S Kharat, Christina R Troll, Areetha D'Souza, Jiyoung Park, P Drew Neufer, Orlando D Schärer, Walter J Chazin

{"title":"XPA tumor variant leads to defects in NER that sensitize cells to cisplatin.","authors":"Alexandra M Blee, Kaitlyn S Gallagher, Hyun-Suk Kim, Mihyun Kim, Suhas S Kharat, Christina R Troll, Areetha D'Souza, Jiyoung Park, P Drew Neufer, Orlando D Schärer, Walter J Chazin","doi":"10.1093/narcan/zcae013","DOIUrl":"10.1093/narcan/zcae013","url":null,"abstract":"Nucleotide excision repair (NER) reduces efficacy of treatment with platinum (Pt)-based chemotherapy by removing Pt lesions from DNA. Previous study has identified that missense mutation or loss of the NER genes Excision Repair Cross Complementation Group 1 and 2 (ERCC1 and ERCC2) leads to improved patient outcomes after treatment with Pt-based chemotherapies. Although most NER gene alterations found in patient tumors are missense mutations, the impact of mutations in the remaining nearly 20 NER genes is unknown. Towards this goal, we previously developed a machine learning strategy to predict genetic variants in an essential NER protein, Xeroderma Pigmentosum Complementation Group A (XPA), that disrupt repair. In this study, we report in-depth analyses of a subset of the predicted variants, including in vitro analyses of purified recombinant protein and cell-based assays to test Pt agent sensitivity in cells and determine mechanisms of NER dysfunction. The most NER deficient variant Y148D had reduced protein stability, weaker DNA binding, disrupted recruitment to damage, and degradation. Our findings demonstrate that tumor mutations in XPA impact cell survival after cisplatin treatment and provide valuable mechanistic insights to improve variant effect prediction. Broadly, these findings suggest XPA tumor variants should be considered when predicting chemotherapy response.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10946055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140159805","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 impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues. tRNA 修饰对癌症翻译的影响：确定新的治疗途径。

NAR cancer Pub Date : 2024-03-12 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae012

Ana M Añazco-Guenkova, Borja Miguel-López, Óscar Monteagudo-García, Raquel García-Vílchez, Sandra Blanco

{"title":"The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues.","authors":"Ana M Añazco-Guenkova, Borja Miguel-López, Óscar Monteagudo-García, Raquel García-Vílchez, Sandra Blanco","doi":"10.1093/narcan/zcae012","DOIUrl":"10.1093/narcan/zcae012","url":null,"abstract":"Recent advancements have illuminated the critical role of RNA modifications in post-transcriptional regulation, shaping the landscape of gene expression. This review explores how tRNA modifications emerge as critical players, fine-tuning functionalities that not only maintain the fidelity of protein synthesis but also dictate gene expression and translation profiles. Highlighting their dysregulation as a common denominator in various cancers, we systematically investigate the intersection of both cytosolic and mitochondrial tRNA modifications with cancer biology. These modifications impact key processes such as cell proliferation, tumorigenesis, migration, metastasis, bioenergetics and the modulation of the tumor immune microenvironment. The recurrence of altered tRNA modification patterns across different cancer types underscores their significance in cancer development, proposing them as potential biomarkers and as actionable targets to disrupt tumorigenic processes, offering new avenues for precision medicine in the battle against cancer.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10928989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140112604","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 AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest. 模拟 DSB 的 AsiDNA™ 诱饵通过 DNA-PK/p53/p21 依赖性 G1/S 停顿保护正常组织免受辐射毒性的伤害。

NAR cancer Pub Date : 2024-03-12 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae011

Anouk Sesink, Margaux Becerra, Jia-Ling Ruan, Sophie Leboucher, Maxime Dubail, Sophie Heinrich, Wael Jdey, Kristoffer Petersson, Charles Fouillade, Nathalie Berthault, Marie Dutreix, Pierre-Marie Girard

{"title":"The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest.","authors":"Anouk Sesink, Margaux Becerra, Jia-Ling Ruan, Sophie Leboucher, Maxime Dubail, Sophie Heinrich, Wael Jdey, Kristoffer Petersson, Charles Fouillade, Nathalie Berthault, Marie Dutreix, Pierre-Marie Girard","doi":"10.1093/narcan/zcae011","DOIUrl":"10.1093/narcan/zcae011","url":null,"abstract":"AsiDNA™, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA™ administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. The lack of normal tissue complication encouraged further examination into the role of AsiDNA™ in normal cells. This research demonstrates the radioprotective properties of AsiDNA™. In vitro, AsiDNA™ induces a DNA-PK/p53/p21-dependent G1/S arrest in normal epithelial cells and fibroblasts that is absent in p53 deficient and proficient tumour cells. This cell cycle arrest improved survival after irradiation only in p53 proficient normal cells. Combined administration of AsiDNA™ with conventional radiotherapy in mouse models of late and early radiation toxicity resulted in decreased onset of lung fibrosis and increased intestinal crypt survival. Similar results were observed following FLASH radiotherapy in standalone or combined with AsiDNA™. Mechanisms comparable to those identified in vitro were detected both in vivo, in the intestine and ex vivo, in precision cut lung slices. Collectively, the results suggest that AsiDNA™ can partially protect healthy tissues from radiation toxicity by triggering a G1/S arrest in normal cells.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10928987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140112552","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

Singleton mutations in large-scale cancer genome studies: uncovering the tail of cancer genome. 大规模癌症基因组研究中的单突变：揭开癌症基因组的尾巴。

NAR cancer Pub Date : 2024-03-12 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae010

Sanket Desai, Suhail Ahmad, Bhargavi Bawaskar, Sonal Rashmi, Rohit Mishra, Deepika Lakhwani, Amit Dutt

{"title":"Singleton mutations in large-scale cancer genome studies: uncovering the tail of cancer genome.","authors":"Sanket Desai, Suhail Ahmad, Bhargavi Bawaskar, Sonal Rashmi, Rohit Mishra, Deepika Lakhwani, Amit Dutt","doi":"10.1093/narcan/zcae010","DOIUrl":"10.1093/narcan/zcae010","url":null,"abstract":"Singleton or low-frequency driver mutations are challenging to identify. We present a domain driver mutation estimator (DOME) to identify rare candidate driver mutations. DOME analyzes positions analogous to known statistical hotspots and resistant mutations in combination with their functional and biochemical residue context as determined by protein structures and somatic mutation propensity within conserved PFAM domains, integrating the CADD scoring scheme. Benchmarked against seven other tools, DOME exhibited superior or comparable accuracy compared to all evaluated tools in the prediction of functional cancer drivers, with the exception of one tool. DOME identified a unique set of 32 917 high-confidence predicted driver mutations from the analysis of whole proteome missense variants within domain boundaries across 1331 genes, including 1192 noncancer gene census genes, emphasizing its unique place in cancer genome analysis. Additionally, analysis of 8799 TCGA (The Cancer Genome Atlas) and in-house tumor samples revealed 847 potential driver mutations, with mutations in tyrosine kinase members forming the dominant burden, underscoring its higher significance in cancer. Overall, DOME complements current approaches for identifying novel, low-frequency drivers and resistant mutations in personalized therapy.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140133687","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

METTL3 as a master regulator of translation in cancer: mechanisms and implications. METTL3 作为癌症翻译的主调节器：机制与影响。

NAR cancer Pub Date : 2024-03-05 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae009

Margalida Esteva-Socias, Francesca Aguilo

{"title":"METTL3 as a master regulator of translation in cancer: mechanisms and implications.","authors":"Margalida Esteva-Socias, Francesca Aguilo","doi":"10.1093/narcan/zcae009","DOIUrl":"10.1093/narcan/zcae009","url":null,"abstract":"Translational regulation is an important step in the control of gene expression. In cancer cells, the orchestration of both global control of protein synthesis and selective translation of specific mRNAs promote tumor cell survival, angiogenesis, transformation, invasion and metastasis. N6-methyladenosine (m6A), the most prevalent mRNA modification in higher eukaryotes, impacts protein translation. Over the past decade, the development of m6A mapping tools has facilitated comprehensive functional investigations, revealing the involvement of this chemical mark, together with its writer METTL3, in promoting the translation of both oncogenes and tumor suppressor transcripts, with the impact being context-dependent. This review aims to consolidate our current understanding of how m6A and METTL3 shape translation regulation in the realm of cancer biology. In addition, it delves into the role of cytoplasmic METTL3 in protein synthesis, operating independently of its catalytic activity. Ultimately, our goal is to provide critical insights into the interplay between m6A, METTL3 and translational regulation in cancer, offering a deeper comprehension of the mechanisms sustaining tumorigenesis.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10914372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140041211","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

SAMHD1 expression contributes to doxorubicin resistance and predicts survival outcomes in diffuse large B-cell lymphoma patients. SAMHD1 的表达会导致多柔比星耐药，并预测弥漫大 B 细胞淋巴瘤患者的生存结果。

IF 3.4

NAR cancer Pub Date : 2024-02-24 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae007

Waaqo Daddacha, Dominique Monroe, Ashley J Schlafstein, Allison E Withers, Elizabeth B Thompson, Diana Danelia, Nho C Luong, Fatmata Sesay, Sandip K Rath, Edidiong R Usoro, Mark E Essien, Andrew T Jung, Jinmeng G Jiang, Jiaxuan Hu, Bijan Mahboubi, Arilyn Williams, Julia E Steinbeck, Xiaofeng Yang, Zachary S Buchwald, William S Dynan, Jeffrey M Switchenko, Baek Kim, Mohammad K Khan, David L Jaye, David S Yu

{"title":"SAMHD1 expression contributes to doxorubicin resistance and predicts survival outcomes in diffuse large B-cell lymphoma patients.","authors":"Waaqo Daddacha, Dominique Monroe, Ashley J Schlafstein, Allison E Withers, Elizabeth B Thompson, Diana Danelia, Nho C Luong, Fatmata Sesay, Sandip K Rath, Edidiong R Usoro, Mark E Essien, Andrew T Jung, Jinmeng G Jiang, Jiaxuan Hu, Bijan Mahboubi, Arilyn Williams, Julia E Steinbeck, Xiaofeng Yang, Zachary S Buchwald, William S Dynan, Jeffrey M Switchenko, Baek Kim, Mohammad K Khan, David L Jaye, David S Yu","doi":"10.1093/narcan/zcae007","DOIUrl":"10.1093/narcan/zcae007","url":null,"abstract":"Diffuse large B-cell lymphoma (DLBCL) is a commonly diagnosed, aggressive non-Hodgkin's lymphoma. While R-CHOP chemoimmunotherapy is potentially curative, about 40% of DLBCL patients will fail, highlighting the need to identify biomarkers to optimize management. SAMHD1 has a dNTPase-independent role in promoting resection to facilitate DNA double-strand break (DSB) repair by homologous recombination. We evaluated the relationship of SAMHD1 levels with sensitivity to DSB-sensitizing agents in DLBCL cells and the association of SAMHD1 expression with clinical outcomes in 79 DLBCL patients treated with definitive therapy and an independent cohort dataset of 234 DLBCL patients. Low SAMHD1 expression, Vpx-mediated, or siRNA-mediated degradation/depletion in DLBCL cells was associated with greater sensitivity to doxorubicin and PARP inhibitors. On Kaplan-Meier log-rank survival analysis, low SAMHD1 expression was associated with improved overall survival (OS), which on subset analysis remained significant only in patients with advanced stage (III-IV) and moderate to high risk (2-5 International Prognostic Index (IPI)). The association of low SAMHD1 expression with improved OS remained significant on multivariate analysis independent of other adverse factors, including IPI, and was validated in an independent cohort. Our findings suggest that SAMHD1 expression mediates doxorubicin resistance and may be an important prognostic biomarker in advanced, higher-risk DLBCL patients.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10894040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975172","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

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。

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":0.0,"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

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