Spatial transcriptomics reveals club cell features and strong CLDN18 expression along the mucinous pathway to invasive mucinous adenocarcinoma
- 1Department of Pathology, School of Medicine Pusan National University Yangsan Republic of Korea
- 2Department of Oral Pathology Dental and Life Science Institute, School of Dentistry, Pusan National University Yangsan Republic of Korea
Abstract
Invasive mucinous adenocarcinoma (IMA) of the lung is a distinct subtype of lung adenocarcinoma with unique clinicopathologic features; however, its histogenesis remains incompletely understood. Although mucinous metaplasia has been suspected as a precursor lesion, direct molecular evidence supporting this progression is limited. In this study, we applied morphology‐guided spatial transcriptomics to investigate epithelial lineage relationships across the mucinous spectrum of lung lesions. Formalin‐fixed, paraffin‐embedded lung tissues from 26 patients were analyzed using the GeoMx digital spatial profiling platform. A total of 118 cytokeratin‐positive regions of interest representing normal bronchioles, bronchiolar metaplasia, mucinous metaplasia, mucinous dysplasia, IMA, nonmucinous terminal respiratory unit–type adenocarcinoma, squamous metaplasia/dysplasia, and squamous cell carcinoma were profiled. Spatial transcriptomic data were integrated with two independent public cohorts and mapped to the Human Lung Cell Atlas for epithelial cell‐type assignment. Unsupervised clustering identified a distinct mucinous cluster comprising IMA and most mucinous dysplasia regions, characterized by enrichment of gastric‐type differentiation markers, including MUC5AC, MUC6, TFF1, TFF2, and CLDN18. Label‐transfer analysis demonstrated that mucinous metaplasia and dysplasia were predominantly associated with club and goblet cell identities, whereas IMAs showed enrichment of club and goblet signatures. In contrast, nonmucinous adenocarcinomas consistently aligned with alveolar type 2 cell identity across all datasets. Immunohistochemistry confirmed uniform CLDN18 expression in IMAs and its absence in nonmucinous adenocarcinomas. These findings provide spatial transcriptomic evidence supporting a club cell–associated mucinous pathway in lung tumorigenesis and identify CLDN18 as a defining molecular feature of IMA. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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BibTeX
@article{park2026spatial,
title = {{Spatial transcriptomics reveals club cell features and strong CLDN18 expression along the mucinous pathway to invasive mucinous adenocarcinoma}},
author = {Joon Young Park and Do Yeon Kim and Hyun Jung Lee and Jung Hee Lee and Hae Ryoun Park and Dong Hoon Shin},
journal = {The Journal of Pathology},
year = {2026},
month = sep,
doi = {10.1002/path.70120},
url = {https://doi.org/10.1002/path.70120},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Spatial transcriptomics reveals club cell features and strong CLDN18 expression along the mucinous pathway to invasive mucinous adenocarcinoma
AU - Joon Young Park
AU - Do Yeon Kim
AU - Hyun Jung Lee
AU - Jung Hee Lee
AU - Hae Ryoun Park
AU - Dong Hoon Shin
PY - 2026
DA - 2026/09/08
JO - The Journal of Pathology
DO - 10.1002/path.70120
UR - https://doi.org/10.1002/path.70120
AB - Invasive mucinous adenocarcinoma (IMA) of the lung is a distinct subtype of lung adenocarcinoma with unique clinicopathologic features; however, its histogenesis remains incompletely understood. Although mucinous metaplasia has been suspected as a precursor lesion, direct molecular evidence supporting this progression is limited. In this study, we applied morphology‐guided spatial transcriptomics to investigate epithelial lineage relationships across the mucinous spectrum of lung lesions. Formalin‐fixed, paraffin‐embedded lung tissues from 26 patients were analyzed using the GeoMx digital spatial profiling platform. A total of 118 cytokeratin‐positive regions of interest representing normal bronchioles, bronchiolar metaplasia, mucinous metaplasia, mucinous dysplasia, IMA, nonmucinous terminal respiratory unit–type adenocarcinoma, squamous metaplasia/dysplasia, and squamous cell carcinoma were profiled. Spatial transcriptomic data were integrated with two independent public cohorts and mapped to the Human Lung Cell Atlas for epithelial cell‐type assignment. Unsupervised clustering identified a distinct mucinous cluster comprising IMA and most mucinous dysplasia regions, characterized by enrichment of gastric‐type differentiation markers, including MUC5AC, MUC6, TFF1, TFF2, and CLDN18. Label‐transfer analysis demonstrated that mucinous metaplasia and dysplasia were predominantly associated with club and goblet cell identities, whereas IMAs showed enrichment of club and goblet signatures. In contrast, nonmucinous adenocarcinomas consistently aligned with alveolar type 2 cell identity across all datasets. Immunohistochemistry confirmed uniform CLDN18 expression in IMAs and its absence in nonmucinous adenocarcinomas. These findings provide spatial transcriptomic evidence supporting a club cell–associated mucinous pathway in lung tumorigenesis and identify CLDN18 as a defining molecular feature of IMA. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
SN - 0022-3417
SN - 1096-9896
ER -