Metabolomics, Transcriptome and Single-Cell RNA Sequencing Analysis of the Metabolic Heterogeneity between Oral Cancer Stem Cells and Differentiated Cancer Cells

Author:

Miao Yuwen1,Wang Pan2ORCID,Huang Jinyan3,Qi Xin2,Liang Yingjiqiong3,Zhao Wenquan2,Wang Huiming1,Lyu Jiong2,Zhu Huiyong2

Affiliation:

1. Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310020, China

2. Department of Stomatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China

3. Biomedical Big Data Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China

Abstract

Understanding the distinct metabolic characteristics of cancer stem cells (CSC) may allow us to better cope with the clinical challenges associated with them. In this study, OSCC cell lines (CAL27 and HSC3) and multicellular tumor spheroid (MCTS) models were used to generate CSC-like cells. Quasi-targeted metabolomics and RNA sequencing were used to explore altered metabolites and metabolism-related genes. Pathview was used to display the metabolites and transcriptome data in a KEGG pathway. The single-cell RNA sequencing data of six patients with oral cancer were analyzed to characterize in vivo CSC metabolism. The results showed that 19 metabolites (phosphoethanolamine, carbamoylphosphate, etc.) were upregulated and 109 metabolites (2-aminooctanoic acid, 7-ketocholesterol, etc.) were downregulated in both MCTS cells. Integration pathway analysis revealed altered activity in energy production (glycolysis, citric cycle, fatty acid oxidation), macromolecular synthesis (purine/pyrimidine metabolism, glycerophospholipids metabolism) and redox control (glutathione metabolism). Single-cell RNA sequencing analysis confirmed altered glycolysis, glutathione and glycerophospholipid metabolism in in vivo CSC. We concluded that CSCs are metabolically inactive compared with differentiated cancer cells. Thus, oral CSCs may resist current metabolic-related drugs. Our result may be helpful in developing better therapeutic strategies against CSC.

Funder

National Natural Science Foundation of China

Publisher

MDPI AG

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