Single-cell RNA sequencing unifies developmental programs of Esophageal and Gastric Intestinal Metaplasia

Karol Nowicki-Osuch, Lizhe Zhuang, Tik Shing Cheung, Emily Black, Neus Masqué-Soler, Ginny Devonshire, Aisling Redmond, Adam Freeman, Massimilliano di Pietro, Nastazja Pilonis, Wladyslaw Januszewicz, Maria O’Donovan, Simon Tavaré, Jacqueline Shields, Rebecca Fitzgerald*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)1346-1363
Number of pages18
JournalCancer discovery
Volume13
Issue number6
DOIs
Publication statusPublished - 17 Mar 2023

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