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Mashup Score: 1
Abstract. Circular extrachromosomal DNA (ecDNA), a common mechanism of oncogene amplification, has been identified as a major contributor to intratumoral heterogeneity and patient outcomes. In a recent publication in Nature Genetics, Chapman and colleagues further explored the role of ecDNA in the context of medulloblastoma. Using whole-genome sequencing, they found that 18% of the patients carry ecDNA amplification across a 468 medulloblastoma patient cohort. The presence of ecDNA was associated with worse survival. Single-cell fluorescence in-situ hybridization imaging and multiomic sequencing revealed that ecDNA copy number displayed a cell-to-cell variability within the sample, contributing to tumor heterogeneity. Furthermore, through sequencing and CRISPRi experiments, the authors uncovered frequent enhancer rewiring events on ecDNA that drive proliferation.
Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
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Mashup Score: 61Passenger gene co-amplifications create collateral therapeutic vulnerabilities in cancer - 4 month(s) ago
Abstract. DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger co-amplifications could create collateral therapeutic vulnerabilities. Through an analysis of >3,000 cancer genomes followed by the interrogation of CRISPR-Cas9 loss-of-function screens across >700 cancer cell lines, we determined that passenger co-amplifications are accompanied by distinct dependency profiles. In a proof-of-principle study, we demonstrate that co-amplification of the bona fide passenger gene DEAD-Box Helicase 1 (DDX1) creates an increased dependency to the mTOR pathway. Interaction proteomics identified tricarboxylic acid (TCA) cycle components as previously unrecognized DDX1 interaction partners. Live-cell metabolomics highlighted that this interaction could impair TCA activity, which in turn resulted in enhanced mTORC1 activity. Consequently, genetic and pharmacologic disruption of mTORC1 resulted in pronounced cell death in vitro and in vivo. Thus, structur
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Mashup Score: 4DON of Hope: Starving Pancreatic Cancer by Glutamine Antagonism - 4 month(s) ago
Abstract. A promising approach to treat solid tumors involves disrupting their reliance on glutamine, a key component for various metabolic processes. Traditional attempts using glutamine inhibitors like 6-diazo-5-oxo-L-norleucine (DON) and CB-839 were unsuccessful, but new hope arises with DRP-104, a pro-drug of DON. This compound effectively targets tumor metabolism while minimizing side effects. In a recent study published in Nature Cancer, Encarnación-Rosado and colleagues demonstrated in pre-clinical models that pancreatic ductal adenocarcinoma (PDAC) responds well to DRP-104, though tumors adapt through the MEK/ERK signaling pathway, which can be countered by the MEK inhibitor trametinib. In a related study, Recouvreux and colleagues found that DON is effective against pancreatic tumors, revealing that PDAC tumors upregulate asparagine synthesis in response to DON, making them susceptible to asparaginase treatment. Both studies underscore the potential of inhibiting glutamine met
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Mashup Score: 4
Abstract. Although there has been a long-standing connection between hyperinsulinemia and cancer development, there is a lack of understanding of the role of the insulin receptor on cells that can become cancerous. In a recent issue of Cell Metabolism, Zhang and colleagues, using a diet-induced obesity mouse model, identified a direct function of insulin receptors on pancreatic acinar cells expressing a KRASG12D mutation in promoting obesity-associated pancreatic cancer. Furthermore, insulin receptor signaling from hyperinsulinemia promoted the secretion of digestive enzymes that contributed to acinar to ductal metaplasia. These findings highlight an important connection between obesity, diabetes, and pancreatic tumor development and suggest potential strategies for obesity-associated cancer prevention targeting the insulin receptor signaling pathways.
Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
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Mashup Score: 0OnlineFirst - 5 month(s) ago
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Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
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Mashup Score: 2OnlineFirst - 5 month(s) ago
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Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
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Mashup Score: 0OnlineFirst - 5 month(s) ago
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Mashup Score: 0Unsatisfactory Fecal Immunochemical Tests for Colorectal Cancer Screening: Prevalence, Reasons, and Subsequent Testing - 6 month(s) ago
AbstractBackground:. Fecal immunochemical test (FIT) is an effective colorectal cancer screening modality. Little is known about prevalence, reasons, and testing after unsatisfactory FIT, or a FIT that cannot be processed by the laboratory due to inadequate stool specimen or incomplete labeling.Methods:. Our retrospective cohort study examined unsatisfactory FIT among average-risk individuals aged 50–74 years in a large, integrated, safety-net health system who completed an index FIT from 2010 to 2019. We determined prevalence of unsatisfactory FIT and categorized reasons hierarchically. We used multivariable logistic regression models to identify factors associated with: (i) unsatisfactory FIT; and (ii) subsequent testing within 15 months of the unsatisfactory FIT.Results:. Of 56,980 individuals completing an index FIT, 10.2% had an unsatisfactory FIT. Reasons included inadequate specimen (51%), incomplete labeling (27%), old specimen (13%), and broken/leaking container (8%). Unsatisf
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Mashup Score: 18
Abstract. How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a guanine nucleotide-binding protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide po
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Mashup Score: 24SUV39H1 Ablation Enhances Long-Term CAR-T Function in Solid Tumors - 6 month(s) ago
Abstract. Failure of adoptive T cell therapies in cancer patients is linked to limited T cell expansion and persistence, even in memory-prone 41BB-(BBz)-based chimeric antigen receptor (CAR) T cells. We show here that BBz-CAR T cell stem/memory differentiation and persistence can be enhanced through epigenetic manipulation of the histone 3 lysine 9 tri-methylation (H3K9me3) pathway. Inactivation of the H3K9 tri-methyltransferase SUV39H1 enhances BBz-CAR T cell long-term persistence, protecting mice against tumor relapses and rechallenges in lung and disseminated solid tumor models up to several months after CAR T cell infusion. Single-cell transcriptomic (scRNAseq) and chromatin opening (scATACseq) analyses of tumor infiltrating CAR T cells show early reprogramming into self-renewing, stem-like populations with decreased expression of dysfunction genes in all T cell subpopulations. Therefore, epigenetic manipulation of H3K9 methylation by SUV39H1 optimizes long-term functional persiste
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#OnlineFirst: Read the In the Spotlight commentary, Defining the role of extrachromosomal DNA, by @roelverhaak and @zhao_dacheng, discussing a recent @NatureGenet paper from @SBPChavezLab. https://t.co/llgvlSpgG4 https://t.co/EE1rk9Vwqb