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ResearchIn-Press PreviewGastroenterologyInflammation Open Access | 10.1172/JCI202488

Single-cell spatial transcriptomics of formalin-fixed, paraffin-embedded biopsies reveals colitis-associated cell networks

Elvira Mennillo,1 Madison L. Lotstein,2 Gyehyun Lee,3 Julian H. Hou,3 Vrinda Johri,4 Donna E. Leet,3 Christina A. Ekstrand,2 Jessica Tsui,4 Jun Yan He,5 Uma Mahadevan,3 Walter L. Eckalbar,4 Ryan M. Gill,6 Christopher J. Bowman,6 David Y. Oh,5 Gabriela K. Fragiadakis,4 Michael G. Kattah,1 and Alexis J. Combes7

1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, United States of America

2Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

3Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

4UCSF CoLabs Initiative, UCSF, San Francisco, United States of America

5Division of Hematology/Oncology, UCSF, San Francisco, United States of America

6Department of Pathology, UCSF, San Francisco, United States of America

7Division of Gastroenterology and Hepatology, UCSF, San Francisco, United States of America

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Published June 9, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI202488.
Copyright © 2026, Mennillo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 9, 2026 - Version history
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Abstract

Imaging-based single-cell spatial transcriptomics (iSCST) on formalin-fixed, paraffin-embedded (FFPE) tissue enables comprehensive analysis of archived specimens while preserving spatial context, critical to an understanding of ulcerative colitis (UC) pathology. Here, we deployed a robust framework for applying iSCST to clinical FFPE mucosal biopsies from patients with UC, immune checkpoint inhibitor-induced (ICI) colitis and healthy controls. iSCST using custom Xenium gene panels enabled precise detection of diverse cell subsets and disease-specific genes. We mapped transcriptionally distinct fibroblast subsets within mucosal niches, including inflammation-associated fibroblasts (IAFs), and identified colitis-specific neighborhoods formed by IAFs, monocytes, and neutrophils. Transcriptional signatures and spatial neighborhoods uncovered through iSCST were associated with vedolizumab (VDZ) response, with non-responders exhibiting either an innate IAF-monocyte-neutrophil signature or adaptive gut-associated lymphoid tissue (GALT) signature, while responders showed enrichment of an epithelial cellular neighborhood. These signatures were validated in an internal and an external dataset, supporting the existence of two distinct archetypes of treatment resistance to VDZ in UC. This iSCST framework provides a powerful approach for analyzing FFPE tissues, offering insights into colitis-associated cellular networks and identifying biomarkers to enhance patient risk stratification in routine clinical workflows.

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  • Version 1 (June 9, 2026): In-Press Preview
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