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Single-cell spatial transcriptomics of formalin-fixed, paraffin-embedded biopsies reveals colitis-associated cell
Elvira Mennillo1,2, Madison L Lotstein3,4, Gyehyun Lee2
1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
The Journal of Clinical Investigation
|June 9, 2026
Summary
Imaging-based single-cell spatial transcriptomics (iSCST) on FFPE tissues reveals distinct cellular neighborhoods in ulcerative colitis (UC). These spatial signatures predict response to vedolizumab (VDZ), identifying two resistance archetypes for improved patient stratification.
Area of Science:
- Gastroenterology and Immunology
- Molecular Pathology
- Biotechnology
Background:
- Ulcerative colitis (UC) pathology is complex and requires understanding of spatial cellular interactions.
- Archived formalin-fixed, paraffin-embedded (FFPE) tissues offer valuable insights but require advanced analytical methods.
- Current methods may not fully capture the spatial context crucial for understanding UC and treatment response.
Purpose of the Study:
- To deploy and validate a framework for imaging-based single-cell spatial transcriptomics (iSCST) on clinical FFPE biopsies from UC patients.
- To identify distinct cellular subsets, spatial neighborhoods, and transcriptional signatures associated with UC and immune checkpoint inhibitor-induced (ICI) colitis.
- To uncover spatial biomarkers predictive of vedolizumab (VDZ) response in UC patients.
Main Methods:
- Application of a robust iSCST framework to FFPE mucosal biopsies from UC patients, ICI colitis patients, and healthy controls.
- Utilized custom Xenium gene panels for precise cell subset and gene detection.
- Mapped fibroblast subsets (e.g., inflammation-associated fibroblasts - IAFs) and identified colitis-specific cellular neighborhoods (e.g., IAFs, monocytes, neutrophils).
Main Results:
- Identified transcriptionally distinct fibroblast subsets and colitis-specific cellular neighborhoods.
- Uncovered spatial signatures associated with vedolizumab (VDZ) response.
- Non-responders showed innate (IAF-monocyte-neutrophil) or adaptive (GALT) signatures, while responders had epithelial cellular neighborhoods.
- Validated these signatures in internal and external datasets, revealing two archetypes of VDZ resistance.
Conclusions:
- The iSCST framework is a powerful tool for analyzing FFPE tissues in colitis research.
- Identified distinct cellular networks and spatial biomarkers in UC.
- The findings support two archetypes of vedolizumab resistance in UC, enabling enhanced patient risk stratification.
