Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions

Yuan-Hung Lo (), Hudson T. Horn, Mo-Fan Huang, Wei-Chieh Yu, Chia-Mei Young, Qing Liu, Madeline Tomaske, Martina Towers, Antonia Dominguez, Michael C. Bassik, Dung-Fang Lee, Lei S. Qi, Jonathan S. Weissman, Jin Chen () and Calvin J. Kuo ()
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Yuan-Hung Lo: University of Texas MD Anderson Cancer Center
Hudson T. Horn: Stanford University School of Medicine
Mo-Fan Huang: UTHealth Houston Graduate School of Biomedical Sciences
Wei-Chieh Yu: University of Texas MD Anderson Cancer Center
Chia-Mei Young: University of Texas MD Anderson Cancer Center
Qing Liu: University of Texas MD Anderson Cancer Center
Madeline Tomaske: Stanford University School of Medicine
Martina Towers: University of Texas MD Anderson Cancer Center
Antonia Dominguez: Stanford University
Michael C. Bassik: Stanford University School of Medicine
Dung-Fang Lee: UTHealth Houston Graduate School of Biomedical Sciences
Lei S. Qi: Stanford University
Jonathan S. Weissman: University of California
Jin Chen: University of Texas Southwestern Medical Center
Calvin J. Kuo: Stanford University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Understanding how genes influence drug responses is critical for advancing personalized cancer treatments. However, identifying these gene-drug interactions in a physiologically relevant human system remains a challenge, as it requires a model that reflects the complexity and heterogeneity among individuals. Here we show that large-scale CRISPR-based genetic screens, including knockout, interference (CRISPRi), activation (CRISPRa), and single-cell approaches, can be applied in primary human 3D gastric organoids to systematically identify genes that affect sensitivity to cisplatin. Our screens uncover genes that modulate cisplatin response. By combining CRISPR perturbations with single-cell transcriptomics, we resolve how genetic alterations interact with cisplatin at the level of individual cells and uncover an unexpected link between fucosylation and cisplatin sensitivity. We identify TAF6L as a regulator of cell recovery from cisplatin-induced cytotoxicity. These results highlight the utility of human organoid models for dissecting gene-drug interactions and offer insights into therapeutic vulnerabilities in gastric cancer.

Date: 2025
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DOI: 10.1038/s41467-025-62818-3

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