Deterministic evolution and stringent selection during preneoplasia
Kasper Karlsson,
Moritz J. Przybilla,
Eran Kotler,
Aziz Khan,
Hang Xu,
Kremena Karagyozova,
Alexandra Sockell,
Wing H. Wong,
Katherine Liu,
Amanda Mah,
Yuan-Hung Lo,
Bingxin Lu,
Kathleen E. Houlahan,
Zhicheng Ma,
Carlos J. Suarez,
Chris P. Barnes,
Calvin J. Kuo and
Christina Curtis ()
Additional contact information
Kasper Karlsson: Stanford University School of Medicine
Moritz J. Przybilla: Stanford University School of Medicine
Eran Kotler: Stanford University School of Medicine
Aziz Khan: Stanford University School of Medicine
Hang Xu: Stanford University School of Medicine
Kremena Karagyozova: Stanford University School of Medicine
Alexandra Sockell: Stanford University School of Medicine
Wing H. Wong: Stanford University School of Medicine
Katherine Liu: Stanford University School of Medicine
Amanda Mah: Stanford University School of Medicine
Yuan-Hung Lo: Stanford University School of Medicine
Bingxin Lu: University College London
Kathleen E. Houlahan: Stanford University School of Medicine
Zhicheng Ma: Stanford University School of Medicine
Carlos J. Suarez: Stanford University School of Medicine
Chris P. Barnes: University College London
Calvin J. Kuo: Stanford University School of Medicine
Christina Curtis: Stanford University School of Medicine
Nature, 2023, vol. 618, issue 7964, 383-393
Abstract:
Abstract The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention1. 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.
Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:618:y:2023:i:7964:d:10.1038_s41586-023-06102-8
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DOI: 10.1038/s41586-023-06102-8
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