Deciphering the heterogeneity of epithelial cells in pancreatic ductal adenocarcinoma: implications for metastasis and immune evasion

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Abstract

Objective

This study examines the cellular heterogeneity of epithelial cells within pancreatic ductal adenocarcinoma (PDAC) and their contributions to tumor progression, metastasis, and immunosuppressive interactions using single-cell RNA sequencing.

Methods

Single-cell RNA-sequencing data from two datasets (GSE154778 and GSE158356) were integrated using the Harmony algorithm, followed by quality control, clustering, and differential gene expression analysis. Distinct subpopulations of epithelial cells were identified, and their gene expression profiles were analyzed. To assess the malignancy of these subpopulations, single-cell copy number variation (CNV) analysis and trajectory analysis were conducted. Additionally, intercellular communication was examined using the CellChat platform.

Results

The analysis revealed pronounced heterogeneity among PDAC epithelial cells, with specific subpopulations exhibiting distinct roles in tumor proliferation, extracellular matrix remodeling, and metastatic dissemination. Subpopulations 4 and 6 were characterized by increased CNV levels and a more malignant phenotype, suggesting an enhanced capacity for metastasis. Single-cell trajectory analysis, along with CellChat, mapped the temporal evolution of epithelial cells, identifying key regulatory genes such as DCBLD2 and JUN. A prognostic model incorporating five key genes, including KLF6, was developed and demonstrated strong predictive accuracy for patient outcomes. Notably, KLF6 emerged as a critical prognostic marker associated with immune modulation, particularly through interactions with M2 macrophages.

Conclusion

The study highlights the pronounced heterogeneity of epithelial cells in PDAC and their distinct contributions to tumor progression, metastasis, and immune modulation. Through single-cell transcriptomic and CNV analyses, we identified epithelial subpopulations with varying malignant potentials and distinct interactions with the tumor microenvironment. Among these, KLF6 emerged as a key regulator associated with immune modulation and metastasis. Our findings emphasize the significance of epithelial cell heterogeneity in shaping pancreatic cancer progression. These insights provide a foundation for future investigations into novel prognostic markers and therapeutic strategies.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12957-025-03793-3.

Related collections

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Author and article information

Contributors

Bin Lin: linbinllb@126.com

Journal

Journal ID (nlm-ta): World J Surg Oncol

Journal ID (iso-abbrev): World J Surg Oncol

Title: World Journal of Surgical Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-7819

Publication date (Electronic): 16 April 2025

Publication date PMC-release: 16 April 2025

Publication date Collection: 2025

Volume: 23

Electronic Location Identifier: 144

Affiliations

[1 ]Department of Hepatopancreatobiliary Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, ( https://ror.org/050s6ns64) Fuzhou, 350014 China

[2 ]Department of Orthodontics, Fujian Medical University Union Hospital, ( https://ror.org/055gkcy74) No. 29 of Xinquan Road, Gulou District, Fuzhou, 350001 China

Article

Publisher ID: 3793

DOI: 10.1186/s12957-025-03793-3

PMC ID: 12004766

PubMed ID: 40240899

SO-VID: 0623d5fa-4634-4f12-a078-6d6b55f1550a

License:

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

History

Date received : 5 February 2025

Date accepted : 29 March 2025

Custom metadata

ScienceOpen disciplines: Surgery

Keywords: copy number variation (cnv),epithelial cell heterogeneity,immune modulation,metastasis,pancreatic cancer,single-cell rna sequencing,tumor microenvironment

Data availability: