NAR cancerPub Date : 2025-02-03eCollection Date: 2025-03-01DOI: 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":"<p><p>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 <i>BRAF</i> 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 <i>Saccharomyces cerevisiae</i> 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.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf002"},"PeriodicalIF":3.4,"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}
{"title":"Specific modulation of 28S_Um2402 rRNA 2'-<i>O</i>-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":"<p><p>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'-<i>O</i>-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.</p>","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}
NAR cancerPub Date : 2025-01-15eCollection Date: 2025-03-01DOI: 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":"<p><p>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.</p>","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}
NAR cancerPub Date : 2024-12-18eCollection Date: 2024-12-01DOI: 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":"<p><p>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.</p>","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}
NAR cancerPub Date : 2024-11-28eCollection Date: 2024-12-01DOI: 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":"<p><p>Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently used to treat <i>BRCA1/2</i> 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 <i>BRCA1/2</i> status showed that in our cohort of 31 ovarian cancer PDX models 22.6% harbored a <i>BRCA1/2</i> alteration (7/31), and 48.3% (15/31) were genomically unstable as measured by copy number alteration analysis. <i>In vivo</i>, PARPi olaparib response was measured in 15 selected PDX models. Functional assessment of HR using <i>ex vivo</i> irradiation-induced RAD51 foci formation identified all olaparib-sensitive PDX models, including four models without <i>BRCA1/2</i> alterations. In contrast, replication fork protection or replication speed in <i>ex vivo</i> tumor tissue did not correlate with olaparib response. Targeted panel sequencing in olaparib-sensitive models lacking <i>BRCA1/2</i> alterations revealed a MUS81 variant as a possible mechanism underlying PARPi sensitivity. Combined, we show that <i>ex vivo</i> RAD51 analysis effectively predicts <i>in vivo</i> olaparib response and revealed a subset of PARPi-sensitive, HR-deficient ovarian cancer PDX models, lacking a BRCA1/2 alteration.</p>","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}
NAR cancerPub Date : 2024-10-16eCollection Date: 2024-12-01DOI: 10.1093/narcan/zcae041
Shen-Hsi Yang, Ibrahim Ahmed, Yaoyong Li, Christopher W Bleaney, Andrew D Sharrocks
{"title":"Massively parallel reporter assays identify enhancer elements in oesophageal Adenocarcinoma.","authors":"Shen-Hsi Yang, Ibrahim Ahmed, Yaoyong Li, Christopher W Bleaney, Andrew D Sharrocks","doi":"10.1093/narcan/zcae041","DOIUrl":"10.1093/narcan/zcae041","url":null,"abstract":"<p><p>Cancer is a disease underpinned by aberrant gene expression. Enhancers are regulatory elements that play a major role in transcriptional control and changes in active enhancer function are likely critical in the pathogenesis of oesophageal adenocarcinoma (OAC). Here, we utilise STARR-seq to profile the genome-wide enhancer landscape in OAC and identify hundreds of high-confidence enhancer elements. These regions are enriched in enhancer-associated chromatin marks, are actively transcribed and exhibit high levels of associated gene activity in OAC cells. These characteristics are maintained in human patient samples, demonstrating their disease relevance. This relevance is further underlined by their responsiveness to oncogenic ERBB2 inhibition and increased activity compared to the pre-cancerous Barrett's state. Mechanistically, these enhancers are linked to the core OAC transcriptional network and in particular KLF5 binding is associated with high level activity, providing further support for a role of this transcription factor in defining the OAC transcriptome. Our results therefore uncover a set of enhancer elements with physiological significance, that widen our understanding of the molecular alterations in OAC and point to mechanisms through which response to targeted therapy may occur.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 4","pages":"zcae041"},"PeriodicalIF":3.4,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484580","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}
NAR cancerPub Date : 2024-09-26eCollection Date: 2024-09-01DOI: 10.1093/narcan/zcae037
Rachel Shoemaker, Mo-Fan Huang, Ying-Si Wu, Cheng-Shuo Huang, Dung-Fang Lee
{"title":"Decoding the molecular symphony: interactions between the m<sup>6</sup>A and p53 signaling pathways in cancer.","authors":"Rachel Shoemaker, Mo-Fan Huang, Ying-Si Wu, Cheng-Shuo Huang, Dung-Fang Lee","doi":"10.1093/narcan/zcae037","DOIUrl":"10.1093/narcan/zcae037","url":null,"abstract":"<p><p>The p53 tumor suppressor gene governs a multitude of complex cellular processes that are essential for anti-cancer function and whose dysregulation leads to aberrant gene transcription, activation of oncogenic signaling and cancer development. Although mutations can occur at any point in the genetic sequence, missense mutations comprise the majority of observed p53 mutations in cancers regardless of whether the mutation is germline or somatic. One biological process involved in both mutant and wild-type p53 signaling is the <i>N</i> <sup>6</sup>-methyladenosine (m<sup>6</sup>A) epitranscriptomic network, a type of post-transcriptional modification involved in over half of all eukaryotic mRNAs. Recently, a significant number of findings have demonstrated unique interactions between p53 and the m<sup>6</sup>A epitranscriptomic network in a variety of cancer types, shedding light on a previously uncharacterized connection that causes significant dysregulation. Cross-talk between wild-type or mutant p53 and the m<sup>6</sup>A readers, writers and erasers has been shown to impact cellular function and induce cancer formation by influencing various cancer hallmarks. Here, this review aims to summarize the complex interplay between the m<sup>6</sup>A epitranscriptome and p53 signaling pathway, highlighting its effects on tumorigenesis and other hallmarks of cancer, as well as identifying its therapeutic implications for the future.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 3","pages":"zcae037"},"PeriodicalIF":3.4,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335463","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}
NAR cancerPub Date : 2024-09-24eCollection Date: 2024-09-01DOI: 10.1093/narcan/zcae038
Anastasia Hale, George-Lucian Moldovan
{"title":"Novel insights into the role of bisphenol A (BPA) in genomic instability.","authors":"Anastasia Hale, George-Lucian Moldovan","doi":"10.1093/narcan/zcae038","DOIUrl":"https://doi.org/10.1093/narcan/zcae038","url":null,"abstract":"<p><p>Bisphenol A (BPA) is a phenolic chemical that has been used for over 50 years in the manufacturing of polycarbonate and polyvinyl chloride plastics, and it is one of the highest volume chemicals produced worldwide. Because BPA can bind to and activate estrogen receptors, studies have mainly focused on the effect of BPA in disrupting the human endocrine and reproductive systems. However, BPA also plays a role in promoting genomic instability and has been associated with initiating carcinogenesis. For example, it has been recently shown that exposure to BPA promotes the formation of single stranded DNA gaps, which may be associated with increased genomic instability. In this review, we outline the mechanisms by which BPA works to promote genomic instability including chromosomal instability, DNA adduct formation, ROS production, and estrogen receptor (ER) activation. Moreover, we define the ways in which BPA promotes both carcinogenesis and resistance to chemotherapy, and we provide critical insights into future directions and outstanding questions in the field.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 3","pages":"zcae038"},"PeriodicalIF":3.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335464","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}
NAR cancerPub Date : 2024-07-16eCollection Date: 2024-09-01DOI: 10.1093/narcan/zcae030
Camilla Coulson-Gilmer, Samantha Littler, Bethany M Barnes, Rosie M Brady, Holda A Anagho, Nisha Pillay, Malini Dey, William Macmorland, Daniel Bronder, Louisa Nelson, Anthony Tighe, Wei-Hsiang Lin, Robert D Morgan, Richard D Unwin, Michael L Nielsen, Joanne C McGrail, Stephen S Taylor
{"title":"Intrinsic PARG inhibitor sensitivity is mimicked by <i>TIMELESS</i> haploinsufficiency and rescued by nucleoside supplementation.","authors":"Camilla Coulson-Gilmer, Samantha Littler, Bethany M Barnes, Rosie M Brady, Holda A Anagho, Nisha Pillay, Malini Dey, William Macmorland, Daniel Bronder, Louisa Nelson, Anthony Tighe, Wei-Hsiang Lin, Robert D Morgan, Richard D Unwin, Michael L Nielsen, Joanne C McGrail, Stephen S Taylor","doi":"10.1093/narcan/zcae030","DOIUrl":"10.1093/narcan/zcae030","url":null,"abstract":"<p><p>A subset of cancer cells are intrinsically sensitive to inhibitors targeting PARG, the poly(ADP-ribose) glycohydrolase that degrades PAR chains. Sensitivity is accompanied by persistent DNA replication stress, and can be induced by inhibition of <i>TIMELESS</i>, a replisome accelerator. However, the nature of the vulnerability responsible for intrinsic sensitivity remains undetermined. To understand PARG activity dependency, we analysed Timeless model systems and intrinsically sensitive ovarian cancer cells. We show that nucleoside supplementation rescues all phenotypes associated with PARG inhibitor sensitivity, including replisome speed and fork stalling, S-phase completion and mitotic entry, proliferation dynamics and clonogenic potential. Importantly nucleoside supplementation restores PARG inhibitor resistance despite the continued presence of PAR chains, indicating that sensitivity does not correlate with PAR levels. In addition, we show that inhibition of thymidylate synthase, an enzyme required for dNTP homeostasis, induces PARG-dependency. Together, these observations suggest that PARG inhibitor sensitivity reflects an inability to control replisome speed and/or maintain helicase-polymerase coupling in response to nucleotide imbalances.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 3","pages":"zcae030"},"PeriodicalIF":3.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11249981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629663","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}
NAR cancerPub Date : 2024-06-19eCollection Date: 2024-06-01DOI: 10.1093/narcan/zcae028
Selina Shiqing K Teh, Kirsten Bowland, Eitan Halper-Stromberg, Akhil Kotwal, Alexis Bennett, Alyza Skaist, Jacqueline Tang, Fidel Cai, Antonella Macoretta, Hong Liang, Hirohiko Kamiyama, Sarah Wheelan, Ming-Tseh Lin, Ralph H Hruban, Chien-Fu Hung, Michael Goldstein, Robert B Scharpf, Nicholas J Roberts, James R Eshleman
{"title":"CRISPR-Cas9 for selective targeting of somatic mutations in pancreatic cancers.","authors":"Selina Shiqing K Teh, Kirsten Bowland, Eitan Halper-Stromberg, Akhil Kotwal, Alexis Bennett, Alyza Skaist, Jacqueline Tang, Fidel Cai, Antonella Macoretta, Hong Liang, Hirohiko Kamiyama, Sarah Wheelan, Ming-Tseh Lin, Ralph H Hruban, Chien-Fu Hung, Michael Goldstein, Robert B Scharpf, Nicholas J Roberts, James R Eshleman","doi":"10.1093/narcan/zcae028","DOIUrl":"10.1093/narcan/zcae028","url":null,"abstract":"<p><p>Somatic mutations are desirable targets for selective elimination of cancer, yet most are found within noncoding regions. We have adapted the CRISPR-Cas9 gene editing tool as a novel, cancer-specific killing strategy by targeting the subset of somatic mutations that create protospacer adjacent motifs (PAMs), which have evolutionally allowed bacterial cells to distinguish between self and non-self DNA for Cas9-induced double strand breaks. Whole genome sequencing (WGS) of paired tumor minus normal (T-N) samples from three pancreatic cancer patients (Panc480, Panc504, and Panc1002) showed an average of 417 somatic PAMs per tumor produced from single base substitutions. Further analyses of 591 paired T-N samples from The International Cancer Genome Consortium found medians of ∼455 somatic PAMs per tumor in pancreatic, ∼2800 in lung, and ∼3200 in esophageal cancer cohorts. Finally, we demonstrated 69-99% selective cell death of three targeted pancreatic cancer cell lines using 4-9 sgRNAs designed using the somatic PAM discovery approach. We also showed no off-target activity from these tumor-specific sgRNAs in either the patient's normal cells or an irrelevant cancer using WGS. This study demonstrates the potential of CRISPR-Cas9 as a novel and selective anti-cancer strategy, and supports the genetic targeting of adult cancers.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 2","pages":"zcae028"},"PeriodicalIF":3.4,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11195629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141447921","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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