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ARTICLE

Glycogen metabolism-mediated intercellular communication in the tumor microenvironment influences liver cancer prognosis

by YANG ZHANG^1,2,#, NANNAN QIN^5,#, XIJUN WANG^6,#, RUI LIANG⁷, QUAN LIU⁴, RUOYI GENG⁸, TIANXIAO JIANG⁸, YUNFEI LIU^8,*, JINWEI LI^3,4,*

1 Graduate School, Kunming Medical University, Kunming, 650000, China
2 Department of Vascular Surgery, Fuwai Yunnan Cardiovascular Hospital, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, 650000, China
3 Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610000, China
4 Department of Neurosurgery, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, 545000, China
5 Department of Gynecology Oncology, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, 545000, China
6 School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China
7 College of Bioengineering, Chongqing University, Chongqing, 400030, China
8 Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, 81377, Germany

* Corresponding Authors: YUNFEI LIU. Email: -muenchen.de; JINWEI LI. Email:
# Co-first author contributions of this article

(This article belongs to the Special Issue: Transcriptome Analysis in Tumor Microenvironment and Tumor Heterogeneity)

Oncology Research 2024, 32(3), 563-576. https://doi.org/10.32604/or.2023.029697

Received 03 March 2023; Accepted 11 September 2023; Issue published 06 February 2024

Abstract

Glycogen metabolism plays a key role in the development of hepatocellular carcinoma (HCC), but the function of glycogen metabolism genes in the tumor microenvironment (TME) is still to be elucidated. Single-cell RNA-seq data were obtained from ten HCC tumor samples totaling 64,545 cells, and 65 glycogen metabolism genes were analyzed by a nonnegative matrix factorization (NMF). The prognosis and immune response of new glycogen TME cell clusters were predicted by using HCC and immunotherapy cohorts from public databases. HCC single-cell analysis was divided into fibroblasts, NT T cells, macrophages, endothelial cells, and B cells, which were separately divided into new cell clusters by glycogen metabolism gene annotation. Pseudo-temporal trajectory analysis demonstrated the temporal differentiation trajectory of different glycogen subtype cell clusters. Cellular communication analysis revealed extensive interactions between endothelial cells with glycogen metabolizing TME cell-related subtypes and different glycogen subtype cell clusters. SCENIC analysis of transcription factors upstream of TME cell clusters with different glycogen metabolism. In addition, TME cell clusters of glycogen metabolism were found to be enriched in expression in CAF subtypes, CD8 depleted, M1, and M2 types. Bulk-seq analysis showed the prognostic significance of glycogen metabolism-mediated TME cell clusters in HCC, while a significant immune response was found in the immunotherapy cohort in patients treated with immune checkpoint blockade (ICB), especially for CAFs, T cells, and macrophages. In summary, our study reveals for the first time that glycogen metabolism mediates intercellular communication in the hepatocellular carcinoma microenvironment while elucidating the anti-tumor mechanisms and immune prognostic responses of different subtypes of cell clusters.

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