Deterministic evolution and stringent selection during preneoplasia

• Published in: Nature (London) 2023-06, Vol.618 (7964), p.383-393
• Main Authors: Karlsson, Kasper, Przybilla, Moritz J., Kotler, Eran, Khan, Aziz, Xu, Hang, Karagyozova, Kremena, Sockell, Alexandra, Wong, Wing H., Liu, Katherine, Mah, Amanda, Lo, Yuan-Hung, Lu, Bingxin, Houlahan, Kathleen E., Ma, Zhicheng, Suarez, Carlos J., Barnes, Chris P., Kuo, Calvin J., Curtis, Christina
• Format: Article
• Language: English
• Subjects: 45/23; 45/91; 631/114/2401; 631/208/69; Adaptation; Aneuploidy; Cancer; Cell Lineage; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Clonal Evolution - genetics; Copy number; Disease Progression; DNA Copy Number Variations; Evolution; Gastric cancer; Genetic transformation; Genomes; Genomic Instability; Humanities and Social Sciences; Humans; Inactivation; Interception; Malignancy; Medicin och hälsovetenskap; Microorganisms; multidisciplinary; Mutation; Organoids; Organoids - metabolism; Organoids - pathology; p53 Protein; Phenotypes; Precancerous Conditions - genetics; Precancerous Conditions - pathology; Preneoplasia; Science; Science (multidisciplinary); Selection, Genetic; Single-Cell Analysis; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumorigenesis; Tumors
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06102-8

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. We model occult preneoplasia by biallelic inactivation of TP53 , a common early event in gastric cancer, in human gastric organoids, the results implying predictability in the earliest stages of tumorigenesis.