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Updated: Jun 4, 2025
An Integrated Raman Spectroscopy and Mass Spectrometry Platform to Study Single-Cell Drug Uptake, Metabolism, and Effects
Published on: January 9, 2020
Single-Cell Mass Spectrometry Studies of Secondary Drug Resistance of Tumor Cells
Guizhen Zhu1,2, Wenmei Zhang1, Yaoyao Zhao1
1Center of Excellence for Environmental Safety and Biological Effects, Department of Chemistry, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China.
Abstract:
Patients with epidermal growth factor receptor mutant nonsmall cell lung cancer (NSCLC) often fail to treat gefitinib because of secondary drug resistance. The development of tumor drug resistance is closely related to variations in cancer cell metabolism. Single-cell metabolomics analysis can provide unique information about tumor drug resistance. Herein, we constructed a platform to study the secondary resistance of tumor cells based on single-cell metabolomics (sSRTC-scM). A gefitinib-resistant NSCLC cell line (PC9GR) was constructed by increasing the dose step by step. The metabolic profiles of parental PC9 cells and PC9GR cells with different drug resistance levels were detected by intact living-cell electrolaunching ionization mass spectrometry at the single-cell level. The data were analyzed by statistical methods such as t-SNE, variance, volcano plot, heat map, and metabolic pathway analysis. Using this platform, we found that the metabolic fingerprints of PC9GR cells can evaluate drug resistance degrees. The metabolic fingerprints continue to be altered with the increase of drug resistance. We revealed 19 metabolic markers of secondary resistance by variance analysis and clarified that the glycerophospholipid metabolic pathway of PC9GR cells changed significantly. In addition, we found that with the increase in drug resistance levels, the heterogeneity of single-cell metabolism became greater and the number of cells with weak drug resistance gradually decreased. This phenomenon can be utilized to illustrate the drug resistance degrees of PC9GR cells. This study provides diagnostic markers for evaluating the drug resistance of tumors and gives new insight into overcoming the secondary resistance of tumors.
Insights
Researchers developed a single-cell metabolomics platform to understand drug resistance in nonsmall cell lung cancer (NSCLC). This approach identified metabolic markers and pathways associated with gefitinib resistance, offering new diagnostic and therapeutic insights.
Area of Science:
- Oncology
- Metabolomics
- Cancer Cell Biology
Background:
- Nonsmall cell lung cancer (NSCLC) with EGFR mutations often develops resistance to gefitinib.
- Tumor drug resistance is linked to alterations in cancer cell metabolism.
- Single-cell metabolomics offers a unique perspective on drug resistance mechanisms.
Purpose of the Study:
- To establish a platform for studying secondary drug resistance in tumor cells using single-cell metabolomics (sSRTC-scM).
- To investigate metabolic changes associated with gefitinib resistance in NSCLC cells.
- To identify potential diagnostic markers for evaluating tumor drug resistance.
Main Methods:
- Constructed a gefitinib-resistant NSCLC cell line (PC9GR).
- Utilized intact living-cell electrospray ionization mass spectrometry for single-cell metabolomics.
- Applied statistical analyses including t-SNE, variance, volcano plots, heat maps, and pathway analysis.
Main Results:
- Developed a platform (sSRTC-scM) capable of evaluating drug resistance degrees through metabolic fingerprints.
- Identified 19 metabolic markers of secondary resistance and significant changes in the glycerophospholipid metabolic pathway.
- Observed increased metabolic heterogeneity and a decrease in weakly resistant cells with rising drug resistance levels.
Conclusions:
- Metabolic fingerprints at the single-cell level can effectively assess tumor drug resistance.
- The study identified key metabolic markers and pathways crucial for understanding and potentially overcoming gefitinib resistance in NSCLC.
- Findings provide novel insights and diagnostic markers for tumor drug resistance evaluation.
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