ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Cancer Cell Biology
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1611951
This article is part of the Research TopicNovel Therapeutic Approaches for Biliary Tract Cancer and Hepatocellular Carcinoma, Volume IIView all 4 articles
Comparative Transcriptomic and Genomic Analysis of Tumor Cells in the Marginal and Center Regions of Tumor Nests in Human Hepatocellular Carcinoma
Provisionally accepted
- 1Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, Shanghai Municipality, China
- 2Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- 3High School Affiliated to Shanghai Jiao Tong University, Jiading Campus, Shanghai, China
- 4Ulink college of Shanghai, Shanghai, China
- 5National Center for Liver Cancer and International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai, China
- 6Molecular Pathology Laboratory, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Background: The tumor nests in solid tumors, including hepatocellular carcinoma (HCC), possess tumor-initiating potential, with the capacity to metastasize and form new metastatic lesions. However, the biological characteristics and heterogeneity of tumor cells at the central and marginal regions of these tumor nests remain poorly understood.Method: Based on pathological tissue sections, data integration and dimensionality reduction, we defined the boundaries and centers of tumor nests and fibrous nodules within 19 spatial transcriptomics (ST) samples from 8 HCC patients. Differential gene expression was analyzed at the single-unit, sample, patient, and pseudobulk levels, followed by Gene Ontology (GO) enrichment analysis. Additionally, spatial copy number variation (CNV) was inferred using inferCNV, and comparisons were made at the single-unit, sample, patient, and pseudobulk levels.Results: Ultimately, 24 tumor nests and 15 liver fibrosis nodules were analyzed. The spatial gene expression patterns of the tumor nests exhibited significant heterogeneity, with gene enrichment analysis revealing upregulation of immune-related pathways (e.g., humoral immune response mediated by circulating immunoglobulin; B cell receptor signaling pathway, etc.) at the tumor nest margins and growth/metabolism-related pathways (e.g., sulfur amino acid metabolic process; proteinogenic amino acid metabolic process, etc.) within the tumor nest center. Similar expression patterns were also observed in liver fibrous nodule samples. CNV and clustering analyses demonstrated transcriptional differences between tumor nests within individual patients, suggesting the evolutionary diversity, or heterogeneity, of tumor nests within the same tumor.Conclusion: Tumor nests exhibit significant transcriptional differentiation along spatial axes: the central regions show high expression of metabolism-related genes, while the marginal regions are enriched in immune-regulatory genes. This pattern is also observed in liver fibrotic nodules. This center-margin functional division may inform rational design of therapeutics that simultaneously modulate metabolism and immune responses.
Keywords: Hepatocellular Carcinoma, Tumor nest, Spatial transcriptomic, fibrotic nodules, heterogeneity
Received: 15 Apr 2025; Accepted: 24 Jun 2025.
Copyright: © 2025 Li, Hu, He, Xu, Wang and He. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Hongyang Wang, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, Shanghai Municipality, China
Yufei He, Molecular Pathology Laboratory, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.