Epigenomic analyses identify FOXM1 as a key regulator of anti-tumor immune response in esophageal adenocarcinoma DOI Creative Commons
Benjamin Ziman, Qian Yang, Yueyuan Zheng

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(2)

Published: Feb. 19, 2024

Unlike most cancer types, the incidence of esophageal adenocarcinoma (EAC) has rapidly escalated in western world over recent decades. Using whole genome bisulfite sequencing (WGBS), we identify transcription factor (TF) FOXM1 as an important epigenetic regulator EAC. plays a critical role cellular proliferation and tumor growth EAC patient-derived organoids cell line models. We ERBB2 upstream expression transcriptional activity FOXM1. Unexpectedly, gene set enrichment analysis (GSEA) unbiased screen reveals prominent anti-correlation between immune response pathways. Indeed, syngeneic mouse models show that inhibits infiltration CD8

Language: Английский

Applications of single-cell RNA sequencing in drug discovery and development DOI Creative Commons
Bram Van de Sande, Joon Sang Lee, Euphemia Mutasa-Gottgens

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 496 - 520

Published: April 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.

Language: Английский

Citations

207
A spatially resolved atlas of the human lung characterizes a gland-associated immune niche DOI Creative Commons
Elo Madissoon, Amanda J. Oliver, Vitalii Kleshchevnikov

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 55(1), P. 66 - 77

Published: Dec. 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.

Language: Английский

Citations

119
Understanding tumour endothelial cell heterogeneity and function from single-cell omics DOI
Qun Zeng, Mira Mousa,

Aisha Shigna Nadukkandy

et al.

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(8), P. 544 - 564

Published: June 22, 2023

Language: Английский

Citations

94
Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets DOI Creative Commons
Shaosen Zhang,

Xinyi Xiao,

Yonglin Yi

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: June 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.

Language: Английский

Citations

62
Advances in diagnosis and management of cancer of the esophagus DOI Open Access
Nathaniel Deboever, Christopher M. Jones, Kohei Yamashita

et al.

BMJ, Journal Year: 2024, Volume and Issue: unknown, P. e074962 - e074962

Published: June 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.

Language: Английский

Citations

46
Deterministic evolution and stringent selection during preneoplasia DOI Creative Commons
Kasper Karlsson, Moritz J. Przybilla, Eran Kotler

et al.

Nature, Journal Year: 2023, Volume and Issue: 618(7964), P. 383 - 393

Published: May 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.

Language: Английский

Citations

45
Kyoto international consensus report on anatomy, pathophysiology and clinical significance of the gastro-oesophageal junction DOI Creative Commons
Kentaro Sugano, Stuart J. Spechler, Emad El‐Omar

et al.

Gut, Journal Year: 2022, Volume and Issue: unknown, P. gutjnl - 327281

Published: June 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.

Language: Английский

Citations

42
Improving outcomes in patients with oesophageal cancer DOI
Manish A. Shah, Nasser K. Altorki,

Pretish Patel

et al.

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 20(6), P. 390 - 407

Published: April 21, 2023

Language: Английский

Citations

42
Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression DOI Creative Commons
Kie Kyon Huang,

Haoran Ma,

Roxanne Hui Heng Chong

et al.

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(12), P. 2019 - 2037.e8

Published: Oct. 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.

Language: Английский

Citations

40
Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia DOI Creative Commons
Karol Nowicki-Osuch, Lizhe Zhuang, Tik Shing Cheung

et al.

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(6), P. 1346 - 1363

Published: March 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.

Language: Английский

Citations

39