Exploring the mechanism of contact-dependent cell-cell communication on chemosensitivity based on single-cell
Yue Jiang1, Xuelian Ren2, Guobin Liu2
1School of Mechanical Engineering and Automation, Northeastern University, Shenyang, 110819, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Abstract:
High-throughput drug screening (HTDS) has significantly reduced the time and cost of new drug development. Nonetheless, contact-dependent cell-cell communication (CDCCC) may impact the chemosensitivity of tumour cells. There is a pressing need for low-cost single-cell HTDS platforms, alongside a deep comprehension of the mechanisms by which CDCCC affects drug efficacy, to fully unveil the efficacy of anticancer drugs. In this study, we develop a microfluidic chip for single-cell HTDS and evaluate the molecular mechanisms impacted by CDCCC using quantitative mass spectrometry-based proteomics. The chip achieves high-quality drug mixing and single-cell capture, with single-cell drug screening results on the chip showing consistency with those on the 96-well plates under varying concentration gradients. Through quantitative proteomic analysis, we deduce that the absence of CDCCC in single tumour cells can enhance their chemoresistance potential, but simultaneously subject them to stronger proliferation inhibition. Additionally, pathway enrichment analysis suggests that CDCCC could impact several signalling pathways in tumour single cells that regulate vital biological processes such as tumour proliferation, adhesion, and invasion. These results offer valuable insights into the potential connection between CDCCC and the chemosensitivity of tumour cells. This research paves the way for the development of single-cell HTDC platforms and holds the promise of advancing tumour personalized treatment strategies.
Insights
We developed a microfluidic chip for single-cell high-throughput drug screening (HTDS) to study how cell communication affects cancer drug efficacy. This platform reveals that blocking cell communication can increase chemoresistance but also inhibit tumor growth.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Pharmacology
Background:
- High-throughput drug screening (HTDS) accelerates drug development but may overlook cell-cell communication effects.
- Contact-dependent cell-cell communication (CDCCC) can influence tumor cell chemosensitivity.
- There is a need for cost-effective single-cell HTDS platforms and understanding CDCCC's impact on drug efficacy.
Purpose of the Study:
- To develop a microfluidic chip for single-cell HTDS.
- To investigate the molecular mechanisms by which CDCCC affects tumor cell chemosensitivity.
- To assess the role of CDCCC in drug efficacy and tumor progression.
Main Methods:
- Development of a microfluidic chip for precise drug mixing and single-cell capture.
- Validation of chip performance against 96-well plate assays.
- Quantitative mass spectrometry-based proteomics to analyze molecular changes.
- Pathway enrichment analysis to identify affected signaling pathways.
Main Results:
- The microfluidic chip demonstrated high-quality single-cell capture and drug screening, consistent with traditional methods.
- Absence of CDCCC in single tumor cells can enhance chemoresistance but also lead to greater proliferation inhibition.
- Proteomic analysis revealed CDCCC impacts signaling pathways regulating tumor proliferation, adhesion, and invasion.
Conclusions:
- CDCCC significantly influences tumor cell chemosensitivity and biological processes.
- The developed single-cell HTDS platform provides insights into CDCCC-mediated drug resistance.
- This research supports the advancement of personalized cancer treatment strategies and single-cell screening technologies.
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