CRISPR/Cas9 Screen in Gastric Cancer Patient‐Derived Organoids Reveals KDM1A‐NDRG1 Axis as a Targetable Vulnerability
Open accessAbstract
Viability CRISPR screens have proven indispensable in parsing genome function. However, their application in new, more physiologically relevant culturing systems like patient‐derived organoids (PDOs) has been much slower. To probe epigenetic contribution to gastric cancer (GC), the third leading cause of cancer‐related deaths worldwide, the first negative selection CRISPR screen in GC PDOs that faithfully preserve primary tumor characteristics is performed. Extensive quality control measurements showing feasibility of CRISPR screens in primary organoid culture are provided. The screen reveals the histone lysine demethylase‐1A (KDM1A) to constitute a GC vulnerability. Both genetic and pharmacological inhibition of KDM1A cause organoid growth retardation. Further, it is shown that most of KDM1A cancer‐supporting functions center on repression of N‐myc downstream regulates gene‐1 (NDRG1). De‐repression of NDRG1 by KDM1A inhibitors (KDM1Ai) causes inhibition of Wnt signaling and a strong G1 cell cycle arrest. Finally, by profiling 20 GC PDOs, it is shown that NDRG1 upregulation predicts KDM1Ai response with 100% sensitivity and 82% specificity in the tested cohort. Thus, this work pioneers the use of negative selection CRISPR screens in patient‐derived organoids, identifies a marker of KDM1Ai response, and accordingly a cohort of patients who may benefit from such therapy.
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CRISPR cutting screens in 3D organoids have been implemented to explore factors such as growth factor dependency for cell growth, identify potential cancer-driving forces, and uncover key genetic events in cell differentiation.
“Even more exciting is the implementation of CRISPR cutting screens in 3D organoids to explore factors such as growth factor dependency for cell growth14–16, identifying potential cancer-driving forces17–19, and uncovering key genetic events in cell differentiation20–22.”
From Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions (2025) · cites this paper as [18]
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p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation
Xia, M., Knezevic, D., & Vassilev, L. T. (2011) · Oncogene · doi:10.1038/onc.2010.413 · Cited by 64 · see citing works
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Cited by
Sorted by citations
Lo, Y.-H., Horn, H. T., Huang, M.-F., Yu, W.-C., Young, C.-M., Liu, Q., Tomaske, M., Towers, M., Dominguez, A., Bassik, M. C., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-62818-3 · Cited by 37 · see citing works
- Authors
- Mircetic, J., Camgöz, A., Abohawya, M., Ding, L., Dietzel, J., Tobar, S. G., Paszkowski‐Rogacz, M., Seidlitz, T., Schmäche, T., Mehnert, M., Sidorova, O., Weitz, J., Buchholz, F., & Stange, D. E.
- Affiliations
- German Cancer Research Center (DE)
- University Hospital Carl Gustav Carus (DE)
- Max Delbrück Center (DE)
- Corresponding author
- Mircetic, Jovan
- Stange, Daniel E.
- ORCID
- Venue
- Small Methods
- Publisher
- Wiley
- Published
- 2023-03-12
- Volume
- 7
- Issue
- 6
- Pages
- e2201605-e2201605
- ISSN
- 2366-9608 (ISSN-L)
- OpenAlex
- W4324017821
- Cited by
- 40
- References
- 2
- Citations by year
- 2026: 15 · 2025: 15 · 2024: 10
- FWCI
- 3.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Small Methods (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Deutsche Krebshilfe
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- gastric cancer, patient-derived organoids, CRISPR-Cas9 screen, LSD1, NDRG1, histone lysine demethylases, Wnt signaling, G1 cell cycle arrest, epigenetic vulnerability, predictive biomarkers, drug response prediction
- MeSH terms
- Humans, Organoids, Stomach Neoplasms, Cell Line, Tumor, Histone Demethylases, CRISPR-Cas Systems
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