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Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
A Cancer Spheroid Array Chip for Selecting Effective Drug
Jae Won Choi1, Sang-Yun Lee2,3, Dong Woo Lee4
1Department of Biomedical Engineering, Konyang University, Daejeon 35365, Korea. zeak3659@naver.com.
Abstract:
A cancer spheroid array chip was developed by modifying a micropillar and microwell structure to improve the evaluation of drugs targeting specific mutations such as phosphor-epidermal growth factor receptor (p-EGFR). The chip encapsulated cells in alginate and allowed cancer cells to grow for over seven days to form cancer spheroids. However, reagents or media used to screen drugs in a high-density spheroid array had to be replaced very carefully, and this was a tedious task. Particularly, the immunostaining of cancer spheroids required numerous steps to replace many of the reagents used for drug evaluation. To solve this problem, we adapted a micropillar and microwell structure to a spheroid array. Thus, culturing cancer spheroids in alginate spots attached to the micropillar allowed us to replace the reagents in the microwell chip with a single fill of fresh medium, without damaging the cancer spheroids. In this study, a cancer spheroid array was made from a p-EGFR-overexpressing cell line (A549 lung cancer cell line). In a 12 by 36 column array chip (25 mm by 75 mm), the spheroid over 100 µm in diameter started to form at day seven and p-EGFR was also considerably overexpressed. The array was used for p-EGFR inhibition and cell viability measurement against seventy drugs, including ten EGFR-targeting drugs. By comparing drug response in the spheroid array (spheroid model) with that in the single-cell model, we demonstrated that the two models showed different responses and that the spheroid model might be more resistant to some drugs, thus narrowing the choice of drug candidates.
Insights
A novel cancer spheroid array chip simplifies drug screening by enabling easy reagent replacement. This chip revealed that spheroid models show different drug responses compared to single-cell models, potentially improving drug candidate selection.
Area of Science:
- Biotechnology
- Cancer Research
- Drug Discovery
Background:
- Evaluating drugs targeting specific mutations like phosphor-epidermal growth factor receptor (p-EGFR) is crucial in cancer therapy.
- Traditional spheroid array chips present challenges in reagent handling and immunostaining, hindering efficient drug screening.
- Developing advanced platforms is necessary to overcome limitations in current cancer spheroid drug evaluation methods.
Purpose of the Study:
- To develop an improved cancer spheroid array chip for efficient drug evaluation targeting specific mutations.
- To overcome the limitations of tedious reagent replacement and potential damage to spheroids in existing array systems.
- To compare drug responses between spheroid models and single-cell models for enhanced drug candidate selection.
Main Methods:
- A cancer spheroid array chip was engineered using a modified micropillar and microwell structure.
- Cancer cells were encapsulated in alginate on micropillars to form spheroids over seven days.
- The chip facilitated simplified reagent replacement through a single-medium fill, preserving spheroid integrity.
Main Results:
- A 12x36 array chip successfully formed p-EGFR-overexpressing A549 lung cancer spheroids (>100 µm diameter) by day seven.
- The array was utilized for p-EGFR inhibition and cell viability assays against seventy drugs, including ten EGFR-targeting agents.
- Significant differences in drug response were observed between the spheroid model and the single-cell model.
Conclusions:
- The developed cancer spheroid array chip offers a more efficient and less damaging method for drug screening.
- Spheroid models demonstrate differential drug responses compared to single-cell models, suggesting increased resistance to certain drugs.
- This platform aids in narrowing down drug candidates by providing a more biologically relevant drug response profile.
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