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Updated: Sep 30, 2025
Multiparametric Tumor Organoid Drug Screening Using Widefield Live-Cell Imaging for Bulk and Single-Organoid Analysis
Published on: December 23, 2022
Organoid screening reveals epigenetic vulnerabilities in human colorectal cancer
Kohta Toshimitsu1,2, Ai Takano1, Masayuki Fujii1,3
1Department of Organoid Medicine, Sakaguchi Laboratory, Keio University School of Medicine, Tokyo, Japan.
Abstract:
Precision oncology presumes an accurate prediction of drug response on the basis of the molecular profile of tumors. However, the extent to which patient-derived tumor organoids recapitulate the response of in vivo tumors to a given drug remains obscure. To gain insights into the pharmacobiology of human colorectal cancer (CRC), we here created a robust drug screening platform for patient-derived colorectal organoids. Application of suspension culture increased organoid scalability, and a refinement of the culture condition enabled incorporation of normal and precursor organoids to high-throughput drug screening. Drug screening identified bromodomain and extra-terminal (BET) bromodomain protein inhibitor as a cancer-selective growth suppressor that targets genes aberrantly activated in CRC. A multi-omics analysis identified an association between checkpoint with forkhead and ring finger domaines (CHFR) silencing and paclitaxel sensitivity, which was further validated by gene engineering of organoids and in xenografts. Our findings highlight the utility of multiparametric validation in enhancing the biological and clinical fidelity of a drug screening system.
Insights
Patient-derived colorectal organoids were used to create a drug screening platform. This platform identified BET inhibitors as effective against colorectal cancer and linked CHFR silencing to paclitaxel sensitivity.
Area of Science:
- Oncology
- Pharmacology
- Genomics
Background:
- Precision oncology relies on predicting drug response from tumor molecular profiles.
- The fidelity of patient-derived tumor organoids in recapitulating in vivo drug responses is not fully understood.
Purpose of the Study:
- To develop a robust drug screening platform using patient-derived colorectal organoids (CRFs).
- To investigate the pharmacobiology of human colorectal cancer (CRC) and identify novel therapeutic targets.
Main Methods:
- Established a scalable suspension culture system for patient-derived colorectal organoids.
- Incorporated normal and precursor organoids into a high-throughput drug screening system.
- Performed multi-omics analysis and gene engineering for validation.
Main Results:
- Identified bromodomain and extra-terminal (BET) bromodomain protein inhibitors as cancer-selective growth suppressors in CRC.
- Discovered an association between checkpoint with forkhead and ring finger domains (CHFR) silencing and enhanced paclitaxel sensitivity.
- Validated findings through gene engineering in organoids and in vivo xenografts.
Conclusions:
- Patient-derived colorectal organoids provide a valuable platform for drug screening and pharmacobiology studies.
- Multiparametric validation is crucial for enhancing the biological and clinical relevance of drug screening systems.
- BET inhibitors and understanding CHFR's role in paclitaxel response offer potential therapeutic strategies for CRC.
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