High-Throughput Cellular Heterogeneity Analysis in Cell Migration at the Single-Cell Level
Mengli Zhou1,2,3, Yushu Ma1,2, Chun-Cheng Chiang1,2
1UPMC Hillman Cancer Center, University of Pittsburgh, 5115 Centre Ave, Pittsburgh, PA, 15232, USA.
Abstract:
Cancer cell migration represents an essential step toward metastasis and cancer deaths. However, conventional drug discovery focuses on cytotoxic and growth-inhibiting compounds rather than inhibitors of migration. Drug screening assays generally measure the average response of many cells, masking distinct cell populations that drive metastasis and resist treatments. Here, this work presents a high-throughput microfluidic cell migration platform that coordinates robotic liquid handling and computer vision for rapidly quantifying individual cellular motility. Using this innovative technology, 172 compounds were tested and a surprisingly low correlation between migration and growth inhibition was found. Notably, many compounds were found to inhibit migration of most cells while leaving fast-moving subpopulations unaffected. This work further pinpoints synergistic drug combinations, including Bortezomib and Danirixin, to stop fast-moving cells. To explain the observed cell behaviors, single-cell morphological and molecular analysis were performed. These studies establish a novel technology to identify promising migration inhibitors for cancer treatment and relevant applications.
Insights
This study introduces a microfluidic platform to screen cancer cell migration inhibitors, finding many drugs don't affect fast-moving cancer cells. It identifies new drug combinations to target these resistant cells, advancing metastasis research.
Area of Science:
- Oncology
- Biotechnology
- Cell Biology
Background:
- Cancer cell migration is crucial for metastasis and mortality.
- Current drug discovery often overlooks migration inhibitors, focusing on cytotoxicity.
- Standard assays mask heterogeneous cell populations driving metastasis and treatment resistance.
Purpose of the Study:
- To develop and utilize a high-throughput microfluidic platform for individual cell migration analysis.
- To screen compounds for their effects on cancer cell migration and growth inhibition.
- To identify effective drug combinations targeting migratory cancer cell subpopulations.
Main Methods:
- High-throughput microfluidic cell migration platform with robotic liquid handling and computer vision.
- Screening of 172 compounds for migration and growth inhibition.
- Single-cell morphological and molecular analysis to understand cell behavior.
Main Results:
- Low correlation observed between migration inhibition and growth inhibition.
- Many compounds inhibited bulk cell migration but spared fast-moving subpopulations.
- Synergistic drug combinations (e.g., Bortezomib and Danirixin) identified to inhibit fast-moving cells.
Conclusions:
- The novel platform enables rapid quantification of individual cellular motility.
- Identified drug candidates and combinations offer new strategies for combating cancer metastasis.
- This technology facilitates the discovery of potent migration inhibitors for cancer therapy.
