TY - JOUR
T1 - Deterministic evolution and stringent selection during preneoplasia
AU - Karlsson, Kasper
AU - Przybilla, Moritz J.
AU - Kotler, Eran
AU - Khan, Aziz
AU - Xu, Hang
AU - Karagyozova, Kremena
AU - Sockell, Alexandra
AU - Wong, Wing H.
AU - Liu, Katherine
AU - Mah, Amanda
AU - Lo, Yuan Hung
AU - Lu, Bingxin
AU - Houlahan, Kathleen E.
AU - Ma, Zhicheng
AU - Suarez, Carlos J.
AU - Barnes, Chris P.
AU - Kuo, Calvin J.
AU - Curtis, Christina
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6/8
Y1 - 2023/6/8
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-023-06102-8
DO - 10.1038/s41586-023-06102-8
M3 - Article
C2 - 37258665
AN - SCOPUS:85160775121
SN - 0028-0836
VL - 618
SP - 383
EP - 393
JO - Nature
JF - Nature
IS - 7964
ER -