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Updated: Jul 26, 2025
High-sensitivity Detection of Micrometastases Generated by GFP Lentivirus-transduced Organoids Cultured from a Patient-derived Colon Tumor
Published on: June 14, 2018
Drug repurposing screening and mechanism analysis based on human colorectal cancer organoids
Yunuo Mao1,2,3, Wei Wang1,2, Jingwei Yang1,2
1School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China.
Abstract:
Colorectal cancer (CRC) is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed. Here, we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original tumors. To efficiently identify repurposed drugs for CRC, we developed a robust organoid-based drug screening system. By combining the repurposed drug library and computation-based drug prediction, 335 drugs were tested and 34 drugs with anti-CRC effects were identified. More importantly, we conducted a detailed transcriptome analysis of drug responses and divided the drug response signatures into five representative patterns: differentiation induction, growth inhibition, metabolism inhibition, immune response promotion, and cell cycle inhibition. The anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft (PDOX) system in vivo. We found that fedratinib, trametinib, and bortezomib exhibited effective anticancer effects. Furthermore, the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated. Our study offers an innovative approach for drug discovery, and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC.
Insights
Researchers developed an organoid drug screening system to identify new colorectal cancer (CRC) treatments. This system identified 34 effective drugs, including fedratinib, trametinib, and bortezomib, offering novel therapeutic strategies.
Area of Science:
- Oncology
- Drug Discovery
- Genomics
Background:
- Colorectal cancer (CRC) is a complex and heterogeneous disease requiring novel therapeutic strategies.
- Existing treatments face challenges due to tumor heterogeneity.
- There is a pressing need for innovative approaches to identify effective CRC therapies.
Purpose of the Study:
- To establish a robust organoid-based drug screening system for colorectal cancer.
- To identify repurposed drugs with anti-CRC activity using this system.
- To analyze drug response signatures and validate findings in vivo.
Main Methods:
- Development of human colorectal cancer tumor-derived organoids mirroring tumor heterogeneity.
- Implementation of an organoid-based drug screening system combining drug libraries and computational prediction.
- Transcriptome analysis to categorize drug response patterns (differentiation, growth inhibition, metabolism, immune response, cell cycle).
- In vivo validation using patient-derived organoids-based xenograft (PDOX) models.
Main Results:
- Screening of 335 drugs identified 34 with anti-CRC effects.
- Five distinct drug response signatures were characterized through transcriptome analysis.
- Fedratinib, trametinib, and bortezomib demonstrated significant anticancer activity in vitro and in vivo.
- Evaluation of concordance between in vitro organoid and in vivo PDOX drug responses.
Conclusions:
- The study presents an innovative organoid-based platform for colorectal cancer drug discovery.
- Identified repurposed drugs and characterized response signatures offer valuable resources for clinical treatment development.
- The findings highlight the potential of organoids and PDOX models in advancing CRC therapeutics.
