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

doi:10.1158/2159-8290.CD-22-0824

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

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

25 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 language	English
Pages (from-to)	1346-1363
Number of pages	18
Journal	Cancer discovery
Volume	13
Issue number	6
DOIs	https://doi.org/10.1158/2159-8290.CD-22-0824
Publication status	Published - 17 Mar 2023

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Nowicki-Osuch, K., Zhuang, L., Cheung, T. S., Black, E., Masqué-Soler, N., Devonshire, G., Redmond, A., Freeman, A., di Pietro, M., Pilonis, N., Januszewicz, W., O’Donovan, M., Tavaré, S., Shields, J., & Fitzgerald, R. (2023). Single-cell RNA sequencing unifies developmental programs of Esophageal and Gastric Intestinal Metaplasia. Cancer discovery, 13(6), 1346-1363. https://doi.org/10.1158/2159-8290.CD-22-0824

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title = "Single-cell RNA sequencing unifies developmental programs of Esophageal and Gastric Intestinal Metaplasia",

abstract = "Intestinal metaplasia in the esophagus (Barrett{\textquoteright}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.",

author = "Karol Nowicki-Osuch and Lizhe Zhuang and Cheung, {Tik Shing} and Emily Black and Neus Masqu{\'e}-Soler and Ginny Devonshire and Aisling Redmond and Adam Freeman and {di Pietro}, Massimilliano and Nastazja Pilonis and Wladyslaw Januszewicz and Maria O{\textquoteright}Donovan and Simon Tavar{\'e} and Jacqueline Shields and Rebecca Fitzgerald",

note = "Publisher Copyright: {\textcopyright}2023 The Authors; Published by the American Association for Cancer Research. Funding Information: This research was supported by the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014). The laboratory of R.C. Fitzgerald is funded by a Programme Grant from the Medical Research Council (MRC/ W014122/1, G111260). Additional infrastructure support was provided from the Cancer Research UK–funded Experimental Cancer Medicine Centre. L. Zhuang was supported by a Cancer Research UK grant (G102382). E.L. Black was supported by the MRC doctoral training program (RG86932). N. Masqu{\'e}-Soler was supported by the Rosetrees Trust (RG85974). K. Nowicki-Osuch and S. Tavar{\'e} were supported in part by the Irving Institute for Cancer Dynamics. K. Nowicki-Osuch was in part supported by the Canada–UK Foundation. We thank all patients, organ donors, and their families who contributed to this study. We thank the Cambridge Biorepository for Translational Medicine for collecting deceased organ donor samples. We thank P. Coupland, K. Kania, and the Cancer Research UK Cambridge Institute Core Genomics facility for scRNA-seq. We thank the Human Research Tissue Bank at Cambridge University Hospital, which is supported by the NIHR Cambridge Biomedical Research Centre, from Addenbrooke{\textquoteright}s Hospital. We thank John C. Marioni for providing access to the Cancer Research UK Cambridge Institute computer cluster. We thank Reed Black for help with the graphic design of Fig. 1A. Funding Information: K. Nowicki-Osuch reports grants from Cancer Research UK and the Canada–UK Foundation during the conduct of the study, and is a visiting scientist at Cambridge University and New York Genome Center and has access to their facilities, including computational clusters. Both entities do not provide financial compensation to Dr. Nowicki-Osuch. L. Zhuang reports grants from the Early Cancer Institute during the conduct of the study. E.L. Black reports grants from the Medical Research Council during the conduct of the study. N. Masqu{\'e}-Soler reports grants from the Rosetrees Trust during the conduct of the study. G. Devonshire reports grants from Cancer Research UK during the conduct of the study. M. di Pietro reports grants from the Medical Research Council during the conduct of the study. S. Tavar{\'e} reports grants from Cancer Research UK during the conduct of the study; other support from New York Genome Center and personal fees from Kallyope, Ipsen, and Totient outside the submitted work; and is affiliated with the Cancer Research UK Cambridge Institute, where he was employed until 2019. S. Tavar{\'e} is a visiting professor and has some research support at the Cancer Research UK Cambridge Institute. J.D. Shields reports grants from the Medical Research Council during the conduct of the study. R.C. Fitzgerald reports licensing cyto-sponge-TFF3 technology to Covidien (now Medtronic) in 2014, and cofounded and is a 3% shareholder in Cyted Ltd, but does not consider either of these relationships relevant to this article. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2023 The Authors; Published by the American Association for Cancer Research.",

year = "2023",

month = mar,

day = "17",

doi = "10.1158/2159-8290.CD-22-0824",

language = "English",

volume = "13",

pages = "1346--1363",

journal = "Cancer discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

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Nowicki-Osuch, K, Zhuang, L, Cheung, TS, Black, E, Masqué-Soler, N, Devonshire, G, Redmond, A, Freeman, A, di Pietro, M, Pilonis, N, Januszewicz, W, O’Donovan, M, Tavaré, S, Shields, J & Fitzgerald, R 2023, 'Single-cell RNA sequencing unifies developmental programs of Esophageal and Gastric Intestinal Metaplasia', Cancer discovery, vol. 13, no. 6, pp. 1346-1363. https://doi.org/10.1158/2159-8290.CD-22-0824

TY - JOUR

T1 - Single-cell RNA sequencing unifies developmental programs of Esophageal and Gastric Intestinal Metaplasia

AU - Nowicki-Osuch, Karol

AU - Zhuang, Lizhe

AU - Cheung, Tik Shing

AU - Black, Emily

AU - Masqué-Soler, Neus

AU - Devonshire, Ginny

AU - Redmond, Aisling

AU - Freeman, Adam

AU - di Pietro, Massimilliano

AU - Pilonis, Nastazja

AU - Januszewicz, Wladyslaw

AU - O’Donovan, Maria

AU - Tavaré, Simon

AU - Shields, Jacqueline

AU - Fitzgerald, Rebecca

N1 - Publisher Copyright: ©2023 The Authors; Published by the American Association for Cancer Research. Funding Information: This research was supported by the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014). The laboratory of R.C. Fitzgerald is funded by a Programme Grant from the Medical Research Council (MRC/ W014122/1, G111260). Additional infrastructure support was provided from the Cancer Research UK–funded Experimental Cancer Medicine Centre. L. Zhuang was supported by a Cancer Research UK grant (G102382). E.L. Black was supported by the MRC doctoral training program (RG86932). N. Masqué-Soler was supported by the Rosetrees Trust (RG85974). K. Nowicki-Osuch and S. Tavaré were supported in part by the Irving Institute for Cancer Dynamics. K. Nowicki-Osuch was in part supported by the Canada–UK Foundation. We thank all patients, organ donors, and their families who contributed to this study. We thank the Cambridge Biorepository for Translational Medicine for collecting deceased organ donor samples. We thank P. Coupland, K. Kania, and the Cancer Research UK Cambridge Institute Core Genomics facility for scRNA-seq. We thank the Human Research Tissue Bank at Cambridge University Hospital, which is supported by the NIHR Cambridge Biomedical Research Centre, from Addenbrooke’s Hospital. We thank John C. Marioni for providing access to the Cancer Research UK Cambridge Institute computer cluster. We thank Reed Black for help with the graphic design of Fig. 1A. Funding Information: K. Nowicki-Osuch reports grants from Cancer Research UK and the Canada–UK Foundation during the conduct of the study, and is a visiting scientist at Cambridge University and New York Genome Center and has access to their facilities, including computational clusters. Both entities do not provide financial compensation to Dr. Nowicki-Osuch. L. Zhuang reports grants from the Early Cancer Institute during the conduct of the study. E.L. Black reports grants from the Medical Research Council during the conduct of the study. N. Masqué-Soler reports grants from the Rosetrees Trust during the conduct of the study. G. Devonshire reports grants from Cancer Research UK during the conduct of the study. M. di Pietro reports grants from the Medical Research Council during the conduct of the study. S. Tavaré reports grants from Cancer Research UK during the conduct of the study; other support from New York Genome Center and personal fees from Kallyope, Ipsen, and Totient outside the submitted work; and is affiliated with the Cancer Research UK Cambridge Institute, where he was employed until 2019. S. Tavaré is a visiting professor and has some research support at the Cancer Research UK Cambridge Institute. J.D. Shields reports grants from the Medical Research Council during the conduct of the study. R.C. Fitzgerald reports licensing cyto-sponge-TFF3 technology to Covidien (now Medtronic) in 2014, and cofounded and is a 3% shareholder in Cyted Ltd, but does not consider either of these relationships relevant to this article. No disclosures were reported by the other authors. Publisher Copyright: © 2023 The Authors; Published by the American Association for Cancer Research.

PY - 2023/3/17

Y1 - 2023/3/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85160968953&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-22-0824

DO - 10.1158/2159-8290.CD-22-0824

M3 - Article

SN - 2159-8274

VL - 13

SP - 1346

EP - 1363

JO - Cancer discovery

JF - Cancer discovery

IS - 6

ER -

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

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