Abstract
Human papillomavirus (HPV)-associated endocervical adenocarcinoma is the second-most common cancer of the uterine cervix. HPV-associated endocervical adenocarcinoma can be classified into histologic Silva patterns of invasion, which are associated with clinical outcome. However, the mechanisms underlying these patterns of invasion are incompletely understood. We used whole transcriptome spatial transcriptomics to examine gene expression differences separately in the tumor epithelium and the surrounding stromal immune microenvironment (SIME). Seven cases were evaluated, focusing on cases with two distinct patterns of invasion within the same tumor, to control for inter-patient heterogeneity. The most strongly upregulated pathways in both higher-risk tumor epithelium and SIME were associated with extracellular matrix (ECM) remodeling. Transcriptomic-based inference of immune cell populations showed an increase in macrophage populations in higher-risk tumor areas, confirmed by immunohistochemistry. Finally, we derived a four-gene signature from genes upregulated in higher-risk tumor epithelium (KRT6A, TNC, LAMC2 and FN1), which was associated with worse clinical outcome in an independent dataset (The Cancer Genome Atlas). Overall, this work demonstrates that ECM remodeling and macrophage presence are important in the progression to high-risk patterns of invasion in HPV-associated endocervical adenocarcinoma. In addition, we established a prognostic four-gene signature that is predictive of poor outcome.
Data availability
All code used in data analysis is available at [https://github.com/MLAxelrod/CervicalCaDSP] (https:/github.com/MLAxelrod/CervicalCaDSP). The datasets generated and analyzed during the current study are available in the Gene Expression Omnibus (GEO) repository, GSE316098.
Abbreviations
- HPV:
-
Human papillomavirus
- SIME:
-
Stromal immune microenvironment
- ECM:
-
Extracellular matrix
- LVSI:
-
Lymphovascular space invasion
- FFPE:
-
Formalin fixed paraffin embedded
- TMAs:
-
Tissue microarrays
- ROIs:
-
Regions of interest
- FDR:
-
False discovery rate
- IHC:
-
Immunohistochemical
- TCGA:
-
The Cancer Genome Atlas
- FIGO:
-
Federation of Gynecology and Obstetrics
- LEEP:
-
Loop electrosurgical excision procedure
- Ais:
-
Adenocarcinoma in situ
- NED:
-
No evidence of disease
- QC:
-
Quality control
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Acknowledgements
We thank the St. Louis University Advanced Spatial Biology and Research Histology Facility (Caroline Murphy and Michelle Brennan, PhD) and the Anatomic and Molecular Pathology Core Lab, Washington University School of Medicine. We also thank the Genome Technology Access Center at the McDonnell Genome Institute at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH.
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This work was supported by Washington University in St. Louis Department of Pathology and Immunology TRPA funding.
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L.S. and M.L.A. designed the study, collected and analyzed the data, and wrote and reviewed the manuscript. R.Z. provided biostatistics consultation. All authors read and approved the final paper.
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L.S. declares business relationships with Pairidex, Inc. (scientific advisory board member), and AstraZeneca (speaker and consultant), but these relationships are not relevant to the current work. M.L.A. and R.Z. do not have any conflicts of interest to declare.
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Axelrod, M.L., Zhou, R. & Sun, L. Spatial transcriptomic landscape of invasion patterns in human papillomavirus-associated endocervical adenocarcinoma. Sci Rep (2026). https://doi.org/10.1038/s41598-026-43717-z
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DOI: https://doi.org/10.1038/s41598-026-43717-z
