Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Nature. 2023 Jun;618(7964):383-393. doi: 10.1038/s41586-023-06102-8. Epub 2023 May 31.
The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention. 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.
人类肿瘤发生的最早事件虽然特征描述较差，但可能为恶性肿瘤的检测和预防提供线索。在这里，我们通过双等位基因失活 TP53（胃癌的常见早期事件）在人类胃类器官中模拟隐匿性癌前病变。通过在 2 年内对多个克隆衍生培养物进行实验进化，建立了这种起始遗传损伤与产生的表型之间的因果关系。TP53 缺失引起进行性非整倍体，包括胃癌中常见的拷贝数改变和结构变异，并有明显的优先顺序。TP53 缺陷型胃类器官的纵向单细胞测序同样表明向恶性转录程序进展。此外，具有表达细胞条码的高通量谱系追踪证明了可重复的动力学，即最初具有共同转录程序的罕见亚克隆反复获得克隆优势。这种用于实验进化的强大平台暴露了严格的选择、克隆干扰和显著程度的恶性前上皮类器官的表型趋同。这些数据意味着在肿瘤发生的最早阶段具有可预测性，并显示出恶性转化的进化限制和障碍，这对早期检测和拦截侵袭性、基因组不稳定的肿瘤具有重要意义。
