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Cited by 174Chromatin Remodeling and CancerCRISPR and Genetic EngineeringCancer Genomics and Diagnostics

A CRISPR/Cas9-Engineered ARID1A -Deficient Human Gastric Cancer Organoid Model Reveals Essential and Nonessential Modes of Oncogenic Transformation

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Lo, Yuan-Hung, Kolahi, Kevin S., Du, Yuhong, Chang, Chiung-Ying, Krokhotin, Andrey, Nair, Ajay, Sobba, Walter D., Karlsson, Kasper +15 more·2021·Cancer Discovery
DOI 10.1158/2159-8290.cd-20-1109PMC PMC8346515

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Abstract

Mutations in ARID1A rank among the most common molecular aberrations in human cancer. However, oncogenic consequences of ARID1A mutation in human cells remain poorly defined due to lack of forward genetic models. Here, CRISPR/Cas9-mediated ARID1A knockout (KO) in primary TP53−/− human gastric organoids induced morphologic dysplasia, tumorigenicity, and mucinous differentiation. Genetic WNT/β-catenin activation rescued mucinous differentiation, but not hyperproliferation, suggesting alternative pathways of ARID1A KO-mediated transformation. ARID1A mutation induced transcriptional regulatory modules characteristic of microsatellite instability and Epstein–Barr virus–associated subtype human gastric cancer, including FOXM1-associated mitotic genes and BIRC5/survivin. Convergently, high-throughput compound screening indicated selective vulnerability of ARID1A-deficient organoids to inhibition of BIRC5/survivin, functionally implicating this pathway as an essential mediator of ARID1A KO-dependent early-stage gastric tumorigenesis. Overall, we define distinct pathways downstream of oncogenic ARID1A mutation, with nonessential WNT-inhibited mucinous differentiation in parallel with essential transcriptional FOXM1/BIRC5-stimulated proliferation, illustrating the general utility of organoid-based forward genetic cancer analysis in human cells. Significance: We establish the first human forward genetic modeling of a commonly mutated tumor suppressor gene, ARID1A. Our study integrates diverse modalities including CRISPR/Cas9 genome editing, organoid culture, systems biology, and small-molecule screening to derive novel insights into early transformation mechanisms of ARID1A-deficient gastric cancers. See related commentary by Zafra and Dow, p. 1327. This article is highlighted in the In This Issue feature, p. 1307

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Authors
Lo, Y.-H., Kolahi, K. S., Du, Y., Chang, C.-Y., Krokhotin, A., Nair, A., Sobba, W. D., Karlsson, K., Jones, S. J., Longacre, T. A., Mah, A. T., Tercan, B., Sockell, A., Xu, H., Seoane, J. A., Chen, J., Shmulevich, I., Weissman, J. S., Curtis, C., Califano, A., Fu, H., Crabtree, G. R., & Kuo, C. J.
Affiliations
  • Stanford Medicine (US)
  • Emory University (US)
  • Howard Hughes Medical Institute (US)
  • Columbia University (US)
  • Institute for Systems Biology (US)
  • 6Division of Oncology, Stanford University School of Medicine, Stanford, California.
Corresponding author
Kuo, Calvin J.
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2021-01-15
Volume
11
Issue
6
Pages
1562-1581
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-20-1109
PMC
PMC8346515
OpenAlex
W3119059732
Cited by
174
References
7
Citations by year
2026: 26 · 2025: 36 · 2024: 36 · 2023: 38 · 2022: 20 · 2021: 18
FWCI
8.74
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH (K00CA212433, R00GM134154, U01CA217875, R35 CA197745, S10 OD012351, S10 OD021764)
  • Swedish Research Council International Postdoctoral Fellowship
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
ARID1A, gastric cancer, gastric organoids, CRISPR/Cas9 knockout, tumor suppressor mutations, oncogenic transformation, Wnt/β-catenin signaling, mucinous differentiation, microsatellite instability, Epstein-Barr virus-associated gastric cancer, FOXM1, small molecule screening
MeSH terms
Cell Transformation, Neoplastic, DNA-Binding Proteins, Humans, Models, Biological, Mutation, Stomach Neoplasms, Transcription Factors, CRISPR-Cas Systems

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