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Updated: Nov 8, 2025
Multiparametric Tumor Organoid Drug Screening Using Widefield Live-Cell Imaging for Bulk and Single-Organoid Analysis
Published on: December 23, 2022
High-content, targeted RNA-seq screening in organoids for drug discovery in colorectal cancer
Maxim Norkin1, Paloma Ordóñez-Morán2, Joerg Huelsken1
1Swiss Institute for Experimental Cancer Research (ISREC), École Polytechnique Fédérale de Lausanne-(EPFL-SV), 1015 Lausanne, Switzerland.
Abstract:
Organoids allow the recapitulation of intestinal homeostasis and cancerogenesis in vitro; however, RNA sequencing (RNA-seq)-based methods for drug screens are missing. We develop targeted organoid sequencing (TORNADO-seq), a high-throughput, high-content drug discovery platform that uses targeted RNA-seq to monitor the expression of large gene signatures for the detailed evaluation of cellular phenotypes in organoids. TORNADO-seq is a fast, highly reproducible time- and cost-effective ($5 per sample) method that can probe cell mixtures and their differentiation state in the intestinal system. We apply this method to isolate drugs that enrich for differentiated cell phenotypes and show that these drugs are highly efficacious against cancer compared to wild-type organoids. Furthermore, TORNADO-seq facilitates in-depth insight into the mode of action of these drugs. Our technology can easily be adapted to many other systems and will allow for more systematic, large-scale, and quantitative approaches to study the biology of complex cellular systems.
Insights
We developed Targeted Organoid Sequencing (TORNADO-seq), a cost-effective RNA-seq method for drug discovery in organoids. This platform identifies potent anti-cancer drugs by analyzing cellular phenotypes and differentiation states.
Area of Science:
- Biotechnology
- Genomics
- Cancer Research
Background:
- Organoids model intestinal homeostasis and cancer in vitro.
- Existing RNA sequencing (RNA-seq) methods are insufficient for high-throughput drug screening in organoids.
Purpose of the Study:
- To develop a novel, high-throughput drug discovery platform for organoid systems.
- To enable detailed evaluation of cellular phenotypes and drug efficacy using targeted RNA-seq.
Main Methods:
- Development of Targeted Organoid Sequencing (TORNADO-seq), a platform utilizing targeted RNA-seq.
- Application of TORNADO-seq to monitor large gene signatures and assess cellular phenotypes in organoids.
- Utilizing TORNADO-seq to identify drugs enriching for differentiated cell phenotypes.
Main Results:
- TORNADO-seq is a fast, reproducible, and cost-effective ($5/sample) method.
- The platform successfully identified drugs highly efficacious against cancer organoids.
- Demonstrated TORNADO-seq's ability to provide in-depth insights into drug mechanisms of action.
Conclusions:
- TORNADO-seq is a powerful tool for drug discovery and phenotypic analysis in organoids.
- The technology can be adapted to various biological systems for large-scale, quantitative studies.
- Identified drugs targeting differentiated cell phenotypes show significant anti-cancer potential.
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