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Mashup Score: 1
Abstract. Colorectal cancer (CRC) is a prevalent cancer type in the United States, affecting both genders and influenced by genetics and environmental factors. The role of the gut microbiome in CRC development and therapy response is a burgeoning field of study. A recent study uncovered that trans-3-indoleacrylic acid (IDA), a microbial metabolite from P. anaerobius, promotes CRC by inhibiting ferroptosis, a type of non-apoptotic cell death driven by unrestricted lipid peroxidation and subsequent membrane damage. IDA activates aryl hydrocarbon receptor (AHR), a nuclear transcription factor, leading to the expression of aldehyde dehydrogenase 1 family member A3 (ALDH1A3). ALDH1A3, known for aldehyde detoxification, also contributes to ferroptosis resistance by generating reduced nicotinamide adenine dinucleotide (NADH), critical for the synthesis of reduced coenzyme Q10 (COQH10) by apoptosis inducing factor mitochondria associated 2 (AIFM2, also known as FSP1). Knocking out AHR, AIFM2,
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Mashup Score: 89Early changes in tumor-naive cell-free methylomes and fragmentomes predict outcomes in pembrolizumab-treated solid tumors - 2 month(s) ago
Abstract. Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab, but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab from a pan-cancer phase II investigator-initiated trial (INSPIRE). We trained a pan-cancer methylation signature using independent methylation array data from The Cancer Genome Atlas to quantify a cancer-specific methylation (CSM) and fragment length score (FLS) for each sample. CSM and FLS are strongly correlated with tumor-informed ctDNA levels. Early kinetics of CSM predict overall survival and progression-free survival, independently of tumor type, PD-L1, and tumor mutation burden. Early kinetics of FLS are associated with overall survival independently of CSM. Our tumor-naïv
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Mashup Score: 62Pan-cancer comparative and integrative analyses of driver alterations using Japanese and international genomic databases - 2 month(s) ago
Abstract. Using 48,627 samples from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), we present a pan-cancer landscape of driver alterations and their clinical actionability in Japanese patients. Comparison with Whites in Genomics Evidence Neoplasia Information Exchange (GENIE) demonstrates high TP53 mutation frequencies in Asians across multiple cancer types. Integration of C-CAT, GENIE, and The Cancer Genome Atlas data reveals many co-occurring and mutually exclusive relationships between driver mutations. At pathway level, mutations in epigenetic regulators frequently co-occur with PI3K pathway molecules. Furthermore, we found significant co-occurring mutations within the epigenetic pathway. Accumulation of mutations in epigenetic regulators causes increased proliferation-related transcriptomic signatures. Loss-of-function of many epigenetic drivers inhibits cell proliferation in their wild-type cell lines, but this effect is attenuated in those harboring mutations
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Mashup Score: 10Adding new dimensions to 3D cancer models - 3 month(s) ago
Abstract. Understanding patient-specific responses to anti-cancer therapies and how individual tumors interact with their tumor microenvironment (TME) is a challenging task. To measure the impact of the TME on diverse and clinically-relevant treatments, Zapatero, Tong, and colleagues coupled patient-derived organoid (PDO) and cancer-associated fibroblast (CAF) co-cultures with high-throughput mass cytometry-based assessment of cell state. Using a newly developed
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Mashup Score: 0Integrated Proteogenomics Uncover Mechanisms of Glioblastoma Evolution, Pointing to Novel Therapeutic Targets. - 3 month(s) ago
Abstract. Nearly all glioblastoma (GBM) patients relapse following standard treatment and eventually succumb to disease. While large scale, integrated multi-omic studies have tremendously advanced the understanding of primary GBM at the cellular and molecular level, the post-therapeutic trajectory and biological properties of recurrent GBM remain poorly understood. This knowledge gap was addressed in a recent Cancer Cell article in which Kim and colleagues report on a highly integrative proteogenomic analysis performed on 123 matched primary and recurrent GBMs that uncovered a dramatic evolutionary shift from a proliferative state at initial diagnosis to the activation of neuronal and synaptogenic pathways at recurrence following therapy. Neuronal transition was characterized by post-translational activation of WNT/PCP signaling and BRAF kinase, while many canonical oncogenic pathways, and EGFR in particular, were downregulated. Parallel multi-omics analyses of patient-derived xenograf
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Mashup Score: 17A metabolic-epigenetic mechanism directs cell fate and therapeutic sensitivity in breast cancer - 3 month(s) ago
Abstract. Over the past decade, studies have increasingly shed light on a reciprocal relationship between cellular metabolism and cell fate, meaning that a cell’s lineage both drives and is governed by its specific metabolic features. A recent study by Zhang and colleagues, published in Cell Metabolism, describes a novel metabolic-epigenetic regulatory axis that governs lineage identity in triple negative breast cancer (TNBC). Among the key findings, the authors demonstrate that the metabolic enzyme pyruvate kinase M2 (PKM2) directly binds to the histone methyltransferase enhancer of zeste homologue 2 (EZH2) in the nucleus to silence expression of a set of genes that includes the mitochondrial carnitine transporter SLC16A9. Perturbation of this metabolic-epigenetic regulatory mechanism induces a metabolic shift away from glycolysis and towards fatty acid oxidation. The ensuing influx of carnitine facilitates the deposition of the activating epigenetic mark H3K27Ac onto the promoter of
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Mashup Score: 1
Abstract. Colorectal cancer (CRC) is a prevalent cancer type in the United States, affecting both genders and influenced by genetics and environmental factors. The role of the gut microbiome in CRC development and therapy response is a burgeoning field of study. A recent study uncovered that trans-3-indoleacrylic acid (IDA), a microbial metabolite from P. anaerobius, promotes CRC by inhibiting ferroptosis, a type of non-apoptotic cell death driven by unrestricted lipid peroxidation and subsequent membrane damage. IDA activates aryl hydrocarbon receptor (AHR), a nuclear transcription factor, leading to the expression of aldehyde dehydrogenase 1 family member A3 (ALDH1A3). ALDH1A3, known for aldehyde detoxification, also contributes to ferroptosis resistance by generating reduced nicotinamide adenine dinucleotide (NADH), critical for the synthesis of reduced coenzyme Q10 (COQH10) by apoptosis inducing factor mitochondria associated 2 (AIFM2, also known as FSP1). Knocking out AHR, AIFM2,
Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
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Mashup Score: 1
Abstract. Macrophages are plastic immune cells that have varying functions dependent on stimulation from their environment. In a recent issue of Immunity, Do and colleagues demonstrated that activating mechanistic target of rapamycin complex 1 signaling in tumor macrophages alters their metabolism, localization, and function. Specifically, these tumor macrophages promote vascular remodeling that develops a hypoxic environment toxic to cancer cells. This culminates in a tangible reduction in tumor burden in a murine model of breast cancer. Their findings reveal a unique strategy to promote vascular remodeling through macrophage polarization and thereby highlight the intimate connections between macrophage metabolism and function. Additionally, their model highlights parallels between tumor progression and wound healing contexts while emphasizing the amplified effect of small perturbations to a tumor ecosystem.
Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
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Mashup Score: 59Pan-cancer comparative and integrative analyses of driver alterations using Japanese and international genomic databases - 3 month(s) ago
Abstract. Using 48,627 samples from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), we present a pan-cancer landscape of driver alterations and their clinical actionability in Japanese patients. Comparison with Whites in Genomics Evidence Neoplasia Information Exchange (GENIE) demonstrates high TP53 mutation frequencies in Asians across multiple cancer types. Integration of C-CAT, GENIE, and The Cancer Genome Atlas data reveals many co-occurring and mutually exclusive relationships between driver mutations. At pathway level, mutations in epigenetic regulators frequently co-occur with PI3K pathway molecules. Furthermore, we found significant co-occurring mutations within the epigenetic pathway. Accumulation of mutations in epigenetic regulators causes increased proliferation-related transcriptomic signatures. Loss-of-function of many epigenetic drivers inhibits cell proliferation in their wild-type cell lines, but this effect is attenuated in those harboring mutations
Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
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Mashup Score: 3
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.
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#OnlineFirst: Read the In the Spotlight commentary, Gut microbiome mediates ferroptosis for CRC development, by Daolin Tang et al. discussing a recent @NatureCellBio paper, from Bo Chu et al. https://t.co/sBWiWPxecw https://t.co/PHs2ohsD94