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A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
Single-cell RNA sequencing reveals the communications between tumor microenvironment components and tumor metastasis
Jiatong Li1, Yang Bai2, He Zhang1
1Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China.
Introduction:
Osteosarcoma is a common type of bone cancer characterized by a poor prognosis due to its metastatic nature. The tumor microenvironment (TME) plays a critical role in tumor metastasis and therapy response. Therefore, our study aims to explore the metastatic mechanism of osteosarcoma, potentially opening new avenues for cancer treatment.
Methods:
In this study, we collected data from the GSE152048, GSE14359, and GSE49003 datasets. Differentially expressed genes (DEGs) were identified in osteosarcoma cases with primary and metastatic features using R software and the limma package. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to investigate metastasis-related genes. A protein-protein interaction (PPI) network was established using the STRING database to further analyze these metastasis-associated genes. The abundances of different cell types with a mixed cell population were estimated using the CIBERSORT approach. The scRNA-seq data were analyzed by the Seurat package in R software, and intercellular communications were elucidated using the CellChat R package.
Results:
In this study, 92 DEGs related to metastasis were identified, including 41 upregulated and 51 downregulated genes in both the GSE14359 and GSE49003 datasets. Metastasis-associated pathways were identified, including those involving the cyclin-dependent protein kinase holoenzyme complex, transferase complex, transferring phosphorus-containing groups, SCF ubiquitin ligase complex, and the serine/threonine protein kinase complex. KEGG and PPI network analyses revealed 15 hub genes, including Skp2, KIF20A, CCNF, TROAP, PHB, CKS1B, MCM3, CCNA2, TRIP13, CENPM, Hsp90AB1, JUN, CKS2, TK1, and KIF4A. Skp2 has been known as an E3 ubiquitin ligase involved in osteosarcoma progression. The proportion of CD8+ T cells was found to be higher in metastatic osteosarcoma tissues, and high expression of PHB was associated with a favorable prognosis in osteosarcoma patients. Additionally, 23 cell clusters were classified into eight cell types, including chondrocytes, MSC, T cells, monocytes, tissue stem cells, neurons, endothelial cells, and macrophages. The 15 hub genes were expressed across various cell types, and interactions between different cell types were observed.
Conclusion:
Our study reveals the intricate communication between tumor microenvironment components and tumor metastasis in osteosarcoma.
Insights
This study identified 92 metastasis-related genes in osteosarcoma, revealing key pathways and 15 hub genes. Findings highlight tumor microenvironment interactions critical for osteosarcoma metastasis and potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Osteosarcoma is a bone cancer with a poor prognosis due to metastasis.
- The tumor microenvironment (TME) significantly influences osteosarcoma progression and treatment response.
Purpose of the Study:
- To investigate the metastatic mechanisms of osteosarcoma.
- To identify potential therapeutic targets by analyzing metastasis-related genes and their interactions within the TME.
Main Methods:
- Utilized public datasets (GSE152048, GSE14359, GSE49003) to identify differentially expressed genes (DEGs) in metastatic osteosarcoma.
- Performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network analyses.
- Employed CIBERSORT and Seurat for cell type abundance estimation and scRNA-seq analysis, and CellChat for intercellular communication.
Main Results:
- Identified 92 metastasis-related DEGs (41 upregulated, 51 downregulated).
- Highlighted key pathways including SCF ubiquitin ligase complex and identified 15 hub genes (e.g., Skp2, KIF20A, CCNF, PHB).
- Observed increased CD8+ T cells in metastatic tissues and identified eight distinct cell types within the TME, with observed interactions.
Conclusions:
- Uncovered complex intercellular communications within the osteosarcoma TME.
- The identified hub genes and pathways offer insights into osteosarcoma metastasis.
- Findings may pave the way for novel therapeutic strategies targeting osteosarcoma metastasis.
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