Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62818-3 |
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| author | 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 Calvin J. Kuo |
| author_facet | 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 Calvin J. Kuo |
| author_sort | Yuan-Hung Lo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ad51621edbb941b9a5cd8674f0233f0f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ad51621edbb941b9a5cd8674f0233f0f2025-08-20T03:46:25ZengNature PortfolioNature Communications2041-17232025-08-0116111810.1038/s41467-025-62818-3Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactionsYuan-Hung Lo0Hudson T. Horn1Mo-Fan Huang2Wei-Chieh Yu3Chia-Mei Young4Qing Liu5Madeline Tomaske6Martina Towers7Antonia Dominguez8Michael C. Bassik9Dung-Fang Lee10Lei S. Qi11Jonathan S. Weissman12Jin Chen13Calvin J. Kuo14Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer CenterDivision of Hematology, Department of Medicine, Stanford University School of MedicineThe University of Texas MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical SciencesDepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer CenterDepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer CenterDepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer CenterDivision of Hematology, Department of Medicine, Stanford University School of MedicineDepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer CenterDepartment of Bioengineering, Stanford UniversityDepartment of Genetics, Stanford University School of MedicineThe University of Texas MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical SciencesDepartment of Bioengineering, Stanford UniversityDepartment of Cellular and Molecular Pharmacology, University of CaliforniaLaboratory of Functional Genomics and Translational Control, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical CenterDivision of Hematology, Department of Medicine, Stanford University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-62818-3 |
| spellingShingle | 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 Calvin J. Kuo Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions Nature Communications |
| title | Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions |
| title_full | Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions |
| title_fullStr | Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions |
| title_full_unstemmed | Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions |
| title_short | Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions |
| title_sort | large scale crispr screening in primary human 3d gastric organoids enables comprehensive dissection of gene drug interactions |
| url | https://doi.org/10.1038/s41467-025-62818-3 |
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