Research Paper Advance Articles
Immune cell senescence and exhaustion promote the occurrence of liver metastasis in colorectal cancer by regulating epithelial-mesenchymal transformation
- 1 The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- 2 The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- 3 Department of Traditional Chinese Medicine, The Sixth Affiliated Hospital, South China University of Technology, Foshan, China
- 4 Department of Oncology, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
- 5 Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
Received: November 6, 2023 Accepted: April 3, 2024 Published: April 26, 2024
https://doi.org/10.18632/aging.205778How to Cite
Copyright: © 2024 Lin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Liver metastasis (LM) stands as a primary cause of mortality in metastatic colorectal cancer (mCRC), posing a significant impediment to long-term survival benefits from targeted therapy and immunotherapy. However, there is currently a lack of comprehensive investigation into how senescent and exhausted immune cells contribute to LM.
Methods: We gathered single-cell sequencing data from primary colorectal cancer (pCRC) and their corresponding matched LM tissues from 16 mCRC patients. In this study, we identified senescent and exhausted immune cells, performed enrichment analysis, cell communication, cell trajectory, and cell-based in vitro experiments to validate the results of single-cell multi-omics. This process allowed us to construct a regulatory network explaining the occurrence of LM. Finally, we utilized weighted gene co-expression network analysis (WGCNA) and 12 machine learning algorithms to create prognostic risk model.
Results: We identified senescent-like myeloid cells (SMCs) and exhausted T cells (TEXs) as the primary senescent and exhausted immune cells. Our findings indicate that SMCs and TEXs can potentially activate transcription factors downstream via ANGPTL4-SDC1/SDC4, this activation plays a role in regulating the epithelial-mesenchymal transformation (EMT) program and facilitates the development of LM, the results of cell-based in vitro experiments have provided confirmation of this conclusion. We also developed and validated a prognostic risk model composed of 12 machine learning algorithms.
Conclusion: This study elucidates the potential molecular mechanisms underlying the occurrence of LM from various angles through single-cell multi-omics analysis in CRC. It also constructs a network illustrating the role of senescent or exhausted immune cells in regulating EMT.
Abbreviations
CRC: Colorectal cancer; mCRC: Metastatic colorectal cancer; LM: Liver metastasis; SASP: Senescence associated secretory phenotype; EMT: Epithelial-mesenchymal transformation; TME: Tumor microenvironment; scRNA-Seq: Single-cell RNA sequencing; pCRC: Primary colorectal cancer; PCA: Principal component analysis; DEGs: Differentially expressed genes; SMCs: Senescent-like myeloid cells; GSEA: Gene set enrichment analysis; GO: Gene ontology; KEGG: Kyoto encyclopedia of genes and genomes; SRGs: Senescence-related genes; Tregs: Regulatory T cells.