3 research outputs found
Identification of Subtypes of Barrett's Esophagus and Esophageal Adenocarcinoma Based on DNA Methylation Profiles and Integration of Transcriptome and Genome Data.
No full textBACKGROUND & AIMS: Esophageal adenocarcinomas (EACs) are heterogeneous and often preceded by Barrett's esophagus (BE). Many genomic changes have been associated with development of BE and EAC, but little is known about epigenetic alterations. We performed epigenetic analyses of BE and EAC tissues and combined these data with transcriptome and genomic data to identify mechanisms that control gene expression and genome integrity. METHODS: In a retrospective cohort study, we collected tissue samples and clinical data from 150 BE and 285 EAC cases from the Oesophageal Cancer Classification and Molecular Stratification consortium in the United Kingdom. We analyzed methylation profiles of all BE and EAC tissues and assigned them to subgroups using non-negative matrix factorization with k-means clustering. Data from whole-genome sequencing and transcriptome studies were then incorporated; we performed integrative methylation and RNA-sequencing analyses to identify genes that were suppressed with increased methylation in promoter regions. Levels of different immune cell types were computed using single-sample gene set enrichment methods. We derived 8 organoids from 8 EAC tissues and tested their sensitivity to different drugs. RESULTS: BE and EAC samples shared genome-wide methylation features, compared with normal tissues (esophageal, gastric, and duodenum; controls) from the same patients and grouped into 4 subtypes. Subtype 1 was characterized by DNA hypermethylation with a high mutation burden and multiple mutations in genes in cell cycle and receptor tyrosine signaling pathways. Subtype 2 was characterized by a gene expression pattern associated with metabolic processes (ATP synthesis and fatty acid oxidation) and lack methylation at specific binding sites for transcription factors; 83% of samples of this subtype were BE and 17% were EAC. The third subtype did not have changes in methylation pattern, compared with control tissue, but had a gene expression pattern that indicated immune cell infiltration; this tumor type was associated with the shortest time of patient survival. The fourth subtype was characterized by DNA hypomethylation associated with structure rearrangements, copy number alterations, with preferential amplification of CCNE1 (cells with this gene amplification have been reported to be sensitive to CDK2 inhibitors). Organoids with reduced levels of MGMT and CHFR expression were sensitive to temozolomide and taxane drugs. CONCLUSIONS: In a comprehensive integrated analysis of methylation, transcriptome, and genome profiles of more than 400 BE and EAC tissues, along with clinical data, we identified 4 subtypes that were associated with patient outcomes and potential responses to therapy
Electrical Stimulation of Cells: Drivers, Technology, and Effects
No full textPublished as part of Chemical Reviews special issue “Electric Fields in Chemistry and Biology”Exposure of cells to electric fields is used in applications as diverse as deep brain stimulation to treat the symptoms of Parkinson's disease, tumor-treating fields to delay the progression of hard-to-treat cancers, and electroporation to deliver genetic materials to cells. It is also used to study the fundamental properties of electrically active cells and to induce changes in cell behavior, such as the directed outgrowth of neurites, that may one day find applications in the clinic. This review discusses some of the effects elicited on cells upon exposure to electric fields, both acutely and at longer time scales, and considers the underlying mechanisms proposed. It also provides an overview of the technology used to study the effects of exposure of cell to electric fields, including the different types of metal/electrolyte interfaces and the electrode materials used in in vitro and in vivo applications. The aim is to bring together concepts from different communities to highlight similarities, identify potential synergies, and create common ground that may lead to cross-fertilization and advances in the field.The authors acknowledge funding from EPSRC (IRC in Targeted Delivery for Hard-to-Treat Cancers EP/S009000/1 and program grant EP/W017091/1), a Horizon Europe UKRI underwrite Innovate grant (COPE-Nano, 10078978), and the NIHR Cambridge Biomedical Research Centre (NIHR203312). KKJ gratefully acknowledges support from the Presidential Scholarship for Postdoctoral studies for women (Tel Aviv University) and the Blavatnik Cambridge Postdoctoral Fellowship. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising.Peer reviewe
