Applications of single-cell RNA sequencing in drug discovery and development

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 22(6), С. 496 - 520

Опубликована: Апрель 28, 2023

Single-cell technologies, particularly single-cell RNA sequencing (scRNA-seq) methods, together with associated computational tools and the growing availability of public data resources, are transforming drug discovery development. New opportunities emerging in target identification owing to improved disease understanding through cell subtyping, highly multiplexed functional genomics screens incorporating scRNA-seq enhancing credentialling prioritization. ScRNA-seq is also aiding selection relevant preclinical models providing new insights into mechanisms action. In clinical development, can inform decision-making via biomarker for patient stratification more precise monitoring response progression. Here, we illustrate how methods being applied key steps discuss ongoing challenges their implementation pharmaceutical industry. There have been significant recent advances development remarkable Ferran colleagues primarily pipeline, from decision-making. Ongoing potential future directions discussed.

Язык: Английский

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A spatially resolved atlas of the human lung characterizes a gland-associated immune niche

Nature Genetics, Год журнала: 2022, Номер 55(1), С. 66 - 77

Опубликована: Дек. 21, 2022

Abstract Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture lung and airways, we profiled five proximal-to-distal locations healthy lungs depth using multi-omic single cell/nuclei (queryable at lungcellatlas.org ). Using computational data integration analysis, extend beyond suspension paradigm discover macro micro-anatomical compartments including previously unannotated types epithelial, vascular, stromal nerve bundle micro-environments. We identify implicate peribronchial fibroblasts disease. Importantly, validate a survival niche for IgA plasma cells airway submucosal glands (SMG). show that gland epithelial recruit B cells, promote longevity antibody secretion locally through expression CCL28, APRIL IL-6. This new ‘gland-associated immune niche’ implications respiratory health.

Язык: Английский

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Understanding tumour endothelial cell heterogeneity and function from single-cell omics

Nature reviews. Cancer, Год журнала: 2023, Номер 23(8), С. 544 - 564

Опубликована: Июнь 22, 2023

Язык: Английский

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Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Июнь 18, 2024

Abstract Tumorigenesis is a multistep process, with oncogenic mutations in normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic and expansion tissues, their transformation into cancer remains rare event, indicating presence of additional driver events for progression to an irreversible, highly heterogeneous, invasive lesion. Recently, researchers are emphasizing mechanisms environmental tumor risk factors epigenetic alterations that profoundly influencing early malignant evolution, independently inducing mutations. Additionally, evolution tumorigenesis reflects multifaceted interplay between cell-intrinsic identities various cell-extrinsic exert selective pressures either restrain uncontrolled proliferation or allow specific clones progress tumors. by which induce both intrinsic cellular competency remodel stress facilitate not fully understood. In this review, we summarize genetic, epigenetic, external events, effects on co-evolution transformed cells ecosystem during initiation evolution. A deeper understanding earliest molecular holds promise translational applications, predicting individuals at high-risk developing strategies intercept transformation.

Язык: Английский

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Advances in diagnosis and management of cancer of the esophagus

BMJ, Год журнала: 2024, Номер unknown, С. e074962 - e074962

Опубликована: Июнь 3, 2024

Abstract Esophageal cancer is the seventh most common malignancy worldwide, with over 470 000 new cases diagnosed each year. Two distinct histological subtypes predominate, and should be considered biologically separate disease entities.1 These are esophageal adenocarcinoma (EAC) squamous cell carcinoma (ESCC). Outcomes remain poor regardless of subtype, patients presenting late stage disease.2 Novel strategies to improve early detection respective precursor lesions, dysplasia, Barrett’s esophagus offer potential outcomes. The introduction a limited number biologic agents, as well immune checkpoint inhibitors, resulting in improvements systemic treatment locally advanced metastatic cancer. developments, coupled minimally invasive surgical endoscopic approaches, adaptive precision radiotherapy technologies, outcomes still further. This review summarizes latest advances diagnosis management cancer, developments understanding biology this disease.

Язык: Английский

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Deterministic evolution and stringent selection during preneoplasia

Nature, Год журнала: 2023, Номер 618(7964), С. 383 - 393

Опубликована: Май 31, 2023

Abstract The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention 1 . Here we model occult preneoplasia by biallelic inactivation of TP53 , a common early event in gastric cancer, organoids. Causal relationships between this initiating genetic lesion resulting phenotypes were established using experimental evolution multiple clonally derived cultures over 2 years. loss elicited progressive aneuploidy, including copy number alterations structural variants prevalent cancers, with evident preferred orders. Longitudinal single-cell sequencing TP53- deficient organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones shared programmes repeatedly attain clonal dominance. This powerful platform for exposes stringent selection, interference marked degree phenotypic convergence premalignant epithelial These data imply predictability the stages tumorigenesis show evolutionary constraints barriers transformation, implications earlier interception aggressive, genome-instable tumours.

Язык: Английский

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Kyoto international consensus report on anatomy, pathophysiology and clinical significance of the gastro-oesophageal junction

Gut, Год журнала: 2022, Номер unknown, С. gutjnl - 327281

Опубликована: Июнь 20, 2022

An international meeting was organised to develop consensus on (1) the landmarks define gastro-oesophageal junction (GOJ), (2) occurrence and pathophysiological significance of cardiac gland, (3) definition junctional zone (GOJZ) (4) causes inflammation, metaplasia neoplasia occurring in GOJZ.

Язык: Английский

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Improving outcomes in patients with oesophageal cancer

Nature Reviews Clinical Oncology, Год журнала: 2023, Номер 20(6), С. 390 - 407

Опубликована: Апрель 21, 2023

Язык: Английский

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Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression

Cancer Cell, Год журнала: 2023, Номер 41(12), С. 2019 - 2037.e8

Опубликована: Окт. 26, 2023

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased cancer (GC) risk. Analyzing 1,256 samples (1,152 IMs) across 692 subjects from prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell spatial profiles highlight changes tissue ecology lineage heterogeneity, an stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, microbial communities normally healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only predicting IMs likely transform GC. By highlighting strategies for accurately identifying patients at high GC risk role dysbiosis progression, our results raise opportunities precision prevention interception.

Язык: Английский

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Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia

Cancer Discovery, Год журнала: 2023, Номер 13(6), С. 1346 - 1363

Опубликована: Март 17, 2023

Intestinal metaplasia in the esophagus (Barrett's IM, or BE-IM) and stomach (GIM) are considered precursors for esophageal gastric adenocarcinoma, respectively. We hypothesize that BE-IM GIM follow parallel developmental trajectories response to differing inflammatory insults. Here, we construct a single-cell RNA-sequencing atlas, supported by protein expression studies, of entire gastrointestinal tract spanning physiologically normal pathologic states including (E-GM), BE-IM, atrophic gastritis, GIM. demonstrate share molecular features, individual cells simultaneously possess transcriptional properties intestinal epithelia, suggesting phenotypic mosaicism. Transcriptionally E-GM resembles gastritis; genetically, it is clonal has lower mutational burden than BE-IM. Finally, show acquire protumorigenic, activated fibroblast microenvironment. These findings suggest can be molecularly similar entities adjacent organs, opening path shared detection treatment strategies. Our data capture gradual transition from phenotype (IM) stomach. Because predispose cancer, this new understanding common trajectory could pave way more unified approach treatment. See related commentary Stachler, p. 1291. This article highlighted In Issue feature, 1275.

Язык: Английский

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