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Cited by 83Cancer Genomics and DiagnosticsEvolution and Genetic DynamicsCancer Cells and Metastasis

Deterministic evolution and stringent selection during preneoplasia

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Karlsson, Kasper, Przybilla, Moritz J., Kotler, Eran, Khan, Aziz, Xu, Hang, Karagyozova, Kremena, Sockell, Alexandra, Wong, Wing H. +10 more·2023·Nature
DOI 10.1038/s41586-023-06102-8PMC PMC10247377
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Abstract

The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention 1. Here we model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over 2 years. TP53 loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single-cell sequencing of TP53-deficient gastric organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programmes repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a marked degree of phenotypic convergence in premalignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and show evolutionary constraints and barriers to malignant transformation, with implications for earlier detection and interception of aggressive, genome-instable tumours.

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  • The TP53/APC double knockout (DKO) organoid line was established by sequentially disrupting TP53 and APC from non-neoplastic human gastric organoids.

    “The TP53/APC double knockout (DKO) organoid line was established in our previous studies by sequentially disrupting TP53 and APC37, two common oncogenic loci in gastric adenocarcinoma38,39, from non-neoplastic human gastric organoids (Fig. S1A).”

    From Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions (2025) · cites this paper as [37]

    In “TP53–/– induces CNAs in defined orders” (page not provided), the paper says it established organoids from non-malignant human gastric tissue and engineered TP53 and APC inactivation in two cultures. It describes the APC hit as “concurrently engineered,” however, so it does not support the claimed sequential disruption. (LLM, conf=0.87)

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  • Our oncogene-engineered human tumor organoids represent a pre-cancerous stage.

    “Finally, our oncogene-engineered human tumor organoids represent a pre-cancerous stage9,37, meaning the gene-specific dependencies and biological processes identified may be distinct to early cancer development as opposed to established tumors.”

    From Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions (2025) · cites this paper as [37]

    The Main section describes CRISPR-engineered human gastric organoids used to model preneoplasia, and the Discussion says the TP53-deficient organoids recapitulate occult preneoplasia. That supports the use of engineered human organoids as a pre-cancer model, but the paper does not establish that the citing authors’ own oncogene-engineered tumor organoids are at that stage. (LLM, conf=0.82)

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Research works printed but not linked: 48

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Authors
Karlsson, K., Przybilla, M. J., Kotler, E., Khan, A., Xu, H., Karagyozova, K., Sockell, A., Wong, W. H., Liu, K., Mah, A., Lo, Y.-H., Lu, B., Houlahan, K. E., Ma, Z., Suarez, C. J., Barnes, C. P., Kuo, C. J., & Curtis, C.
Affiliations
  • Science for Life Laboratory (SE)
  • University of Cambridge (GB)
  • Stanford Medicine (US)
  • University College London (GB)
  • Chan Zuckerberg Biohub San Francisco (US)
Corresponding author
Curtis, Christina
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-05-31
Volume
618
Issue
7964
Pages
383-393
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-023-06102-8
PMC
PMC10247377
OpenAlex
W4378903458
Cited by
83
References
57
Citations by year
2026: 22 · 2025: 28 · 2024: 19 · 2023: 14
FWCI
10.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (K00CA212433, U01CA217851, K99CA263014, P30CA124435, R00CA263014, DP1CA238296)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U01DK085527)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
p53 inactivation, gastric cancer, preneoplasia, gastric organoids, experimental evolution, clonal interference, aneuploidy, copy number alterations, structural variants, clonal dominance, lineage tracing, carcinogenesis, phenotypic convergence, genomic instability, early cancer detection
MeSH terms
Aneuploidy, Cell Transformation, Neoplastic, Humans, Mutation, Organoids, Precancerous Conditions, Selection, Genetic, Stomach Neoplasms, Tumor Suppressor Protein p53, Disease Progression, Cell Lineage, Genomic Instability, DNA Copy Number Variations, Single-Cell Analysis, Clonal Evolution

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