Concerted changes in Epithelium and Stroma: a multi-scale, multi-omics analysis of progression from Barrett's Esophagus to adenocarcinoma

Michael K Strasser¹, David L Gibbs¹, Philippe Gascard², Joanna Bons³, John W Hickey⁴, Deng Pan², Joseph A Caruso², Xianhong Wang², Chira Chen-Tanyolac², Rosemary Bai², Christian M Schürch⁵, Yuqi Tan⁶, Sarah Black⁶, Pauline Chu⁷, Alican Ozkan⁸, Nathan Basisty⁹, Veena Sangwan¹⁰, Jacob Rose³, Samah Shah³, Jordan B Burton³, Sophie Camilleri-Broet¹¹, Pierre Olivier Fiset¹¹, Nicholas Bertos¹⁰, Julie Berube¹⁰, Haig Djambazian¹², Rui Li¹², Spyridon Oikonomopoulos¹², Daffolyn Rachael Fels Elliott¹³, Sarah Vernovsky⁸, Elee Shimshoni⁸, Deborah Collyar¹⁴, Ann Russell¹⁵, Jiannis Ragoussis¹⁶, Matthew D Stachler², James R Goldenring¹⁷, Stuart A C McDonald¹⁸, Donald E Ingber¹⁹, Birgit Schilling²⁰, Garry P Nolan²¹, Thea D Tlsty²², Sui Huang²³, Lorenzo E Ferri²⁴

Affiliations

¹ Institute for Systems Biology, Seattle, WA 98109, USA.
² Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
³ The Buck Institute for Research on Aging, Novato, CA 94945, USA.
⁴ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27705, USA.
⁵ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen 72076, Germany; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany.
⁶ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215, USA.
⁹ The Buck Institute for Research on Aging, Novato, CA 94945, USA; National Institute on Aging, NIH, Baltimore, MD 21224, USA.
¹⁰ Division of Thoracic and Upper Gastrointestinal Surgery, Montreal General Hospital, McGill University Health Centre, Montreal, QC H3G 1A4, Canada.
¹¹ Division of Pathology, McGill University Health Center, Montreal, QC H4A 3J1, Canada.
¹² McGill Genome Centre, Victor Phillip Dahdaleh Institute of Genomic Medicine, Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada.
¹³ Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
¹⁴ Patient Advocates in Research, Danville, CA 94506, USA.
¹⁵ National Cancer Research Institute, London E20 1JQ, UK.
¹⁶ McGill Genome Centre, Victor Phillip Dahdaleh Institute of Genomic Medicine, Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada; Department of Bioengineering, Mcgill University, Monreal, QC H3A 0E9, Canada.
¹⁷ Nashville VA Medical Center and Section of Surgical Sciences, Department of Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹⁸ Centre for Cancer Evolution, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
¹⁹ Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215, USA; Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA 02138, USA. Electronic address: don.ingber@wyss.harvard.edu.
²⁰ The Buck Institute for Research on Aging, Novato, CA 94945, USA. Electronic address: bschilling@buckinstitute.org.
²¹ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: gnolan@drowlab.com.
²² Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: thea.tlsty@ucsf.edu.
²³ Institute for Systems Biology, Seattle, WA 98109, USA. Electronic address: sui.huang@isbscience.org.
²⁴ Division of Thoracic and Upper Gastrointestinal Surgery, Montreal General Hospital, McGill University Health Centre, Montreal, QC H3G 1A4, Canada. Electronic address: lorenzo.ferri@mcgill.ca.

PMID: 40695287
PMCID: PMC12327839 (available on 2026-07-21)
DOI: 10.1016/j.devcel.2025.06.034

Concerted changes in Epithelium and Stroma: a multi-scale, multi-omics analysis of progression from Barrett's Esophagus to adenocarcinoma

Michael K Strasser et al. Dev Cell. 2025.

. 2025 Oct 20;60(20):2807-2824.e7.

doi: 10.1016/j.devcel.2025.06.034. Epub 2025 Jul 21.

Authors

Affiliations

¹ Institute for Systems Biology, Seattle, WA 98109, USA.
² Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
³ The Buck Institute for Research on Aging, Novato, CA 94945, USA.
⁴ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27705, USA.
⁵ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen 72076, Germany; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany.
⁶ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215, USA.
⁹ The Buck Institute for Research on Aging, Novato, CA 94945, USA; National Institute on Aging, NIH, Baltimore, MD 21224, USA.
¹⁰ Division of Thoracic and Upper Gastrointestinal Surgery, Montreal General Hospital, McGill University Health Centre, Montreal, QC H3G 1A4, Canada.
¹¹ Division of Pathology, McGill University Health Center, Montreal, QC H4A 3J1, Canada.
¹² McGill Genome Centre, Victor Phillip Dahdaleh Institute of Genomic Medicine, Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada.
¹³ Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
¹⁴ Patient Advocates in Research, Danville, CA 94506, USA.
¹⁵ National Cancer Research Institute, London E20 1JQ, UK.
¹⁶ McGill Genome Centre, Victor Phillip Dahdaleh Institute of Genomic Medicine, Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada; Department of Bioengineering, Mcgill University, Monreal, QC H3A 0E9, Canada.
¹⁷ Nashville VA Medical Center and Section of Surgical Sciences, Department of Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹⁸ Centre for Cancer Evolution, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
¹⁹ Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215, USA; Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA 02138, USA. Electronic address: don.ingber@wyss.harvard.edu.
²⁰ The Buck Institute for Research on Aging, Novato, CA 94945, USA. Electronic address: bschilling@buckinstitute.org.
²¹ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: gnolan@drowlab.com.
²² Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: thea.tlsty@ucsf.edu.
²³ Institute for Systems Biology, Seattle, WA 98109, USA. Electronic address: sui.huang@isbscience.org.
²⁴ Division of Thoracic and Upper Gastrointestinal Surgery, Montreal General Hospital, McGill University Health Centre, Montreal, QC H3G 1A4, Canada. Electronic address: lorenzo.ferri@mcgill.ca.

PMID: 40695287
PMCID: PMC12327839 (available on 2026-07-21)
DOI: 10.1016/j.devcel.2025.06.034

Abstract

Esophageal adenocarcinoma arises from Barrett's esophagus, a metaplastic condition. Multi-omics profiling, integrating single-cell transcriptomics, extracellular matrix proteomics, tissue mechanics and spatial proteomics of the paths of progression from squamous epithelium through metaplasia, dysplasia to adenocarcinoma, in 107 samples from 26 patients in two independent cohorts, defined shared and patient-specific progression characteristics. Metaplastic replacement of epithelial cell composition and architecture was paralleled by changes in stromal cells, extracellular matrix (ECM) and tissue stiffness. This change in pre-cancerous metaplasia was already accompanied by appearance of fibroblasts with the molecular characteristics of carcinoma-associated fibroblasts. These fibroblasts produced the immunosuppressive protein POSTN, whose expression shifted from vascular to stromal cells, consistent with the emergence of an immunosuppressive microenvironment evident in cell neighborhoods enriched for immunoregulatory NK and Treg cells. Thus, Barrett's esophagus progresses as a coordinated multi-component system, supporting treatment paradigms that go beyond targeting cancerous cells to incorporate stromal reprogramming.

Keywords: Barrett’s esophagus; CODEX; ECM proteomics; copy number variation; esophageal adenocarcinoma; metaplasia; scRNA-seq.

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Conflict of interest statement

Declaration of interests G.P.N. has equity in and is a scientific advisory board member of Akoya Biosciences, Inc. C.M.S. is a cofounder and shareholder of Vicinity Bio GmbH, and on the scientific advisory board of and has received research funding from Enable Medicine, Inc., all outside the current work.

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Concerted changes in Epithelium and Stroma: a multi-scale, multi-omics analysis of progression from Barrett's Esophagus to adenocarcinoma

Affiliations

Concerted changes in Epithelium and Stroma: a multi-scale, multi-omics analysis of progression from Barrett's Esophagus to adenocarcinoma

Authors

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Abstract

Conflict of interest statement

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