posted on 2023-06-02, 08:20authored byKarol Nowicki-Osuch, Lizhe Zhuang, Tik Shing Cheung, Emily L. Black, Neus Masqué-Soler, Ginny Devonshire, Aisling M. Redmond, Adam Freeman, Massimilliano di Pietro, Nastazja Pilonis, Wladyslaw Januszewicz, Maria O'Donovan, Simon Tavaré, Jacqueline D. Shields, Rebecca C. Fitzgerald
<p>Gastric and esophageal IM are enriched for extracellular matrix–depositing subtypes of fibroblasts. <b>A,</b> UMAP of fibroblast-like cells (cluster 13 in Supplementary Fig. S1) with fibroblast-specific clusters highlighted. <b>B,</b> UMAP of fibroblast-like cells (cluster 13 in Supplementary Fig. S1) with manually annotated cell types derived from Davidson et al. (<a href="#bib38" target="_blank">38</a>). <b>C,</b> UMAP of fibroblast-like cells (cluster 13 in Supplementary Fig. S1) with the contribution of individual tissue type highlighted. <b>D,</b> Bubble plot of top five genes identified in the differential analysis between the fibroblast-specific cell clusters. <b>E,</b> Bubble plot of genes identified as markers of early fibroblast development by Davidson et al. (<a href="#bib38" target="_blank">38</a>). <b>F,</b> Contribution of cell types derived from Davidson et al. (<a href="#bib38" target="_blank">38</a>) to cell counts from individual tissue types. The tissues originate from three studies: (i) Nowicki-Osuch and Zhuang et al. (<a href="#bib4" target="_blank">4</a>) and this study, (ii) Sathe et al. (<a href="#bib62" target="_blank">62</a>), and (iii) Zhang et al. (<a href="#bib61" target="_blank">61</a>). For tissue for which patient status could be identified, the tissue was split into healthy and disease states. NGB samples are adjacent to gastric cancer samples. <b>G,</b> Proportion of each subtype in total S1/S2/S3 fibroblasts derived from IF staining of E-GM, BE-IM, and GIM. <b>H,</b> Representative IF staining of E-GM, BE-IM, and GIM of S1 (CD34<sup>+</sup>CD31<sup>−</sup>), S2 (POSTN<sup>+</sup>aSMA<sup>−</sup>), and S3 (aSMA<sup>+</sup>) fibroblasts. <b>I,</b> Schematic summary of unified developmental trajectories between BE-IM and GIM.</p>
Funding
Cancer Research UK (CRUK)
Medical Research Council (MRC)
Foundation for Canadian Studies in the United Kingdom (Canada-UK Foundation)
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.
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.See related commentary by Stachler, p. 1291.This article is highlighted in the In This Issue feature, p. 1275