2023/07/19
论文
论文标题：Deterministic evolution and stringent selection during preneoplasia
作者：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
期刊：Nature
发表时间：2023/05/31
数字识别码：10.1038/s41586-023-06102-8
摘要：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.
参考资料：
[1] Cancer's origin story features predictable plot line, researchers find. Retrieved July 14, 2023 from https://medicalxpress.com/news/2 ... ures-plot-line.html
[2] Kasper Karlsson et al, Deterministic evolution and stringent selection during preneoplasia, Nature (2023). DOI: 10.1038/s41586-023-06102-8
