近年来，患者源性胰腺癌器官结构培养的建立为研究人员提供了一种令人兴奋的机会，可以在一种紧密模拟肿瘤的模型上进行广泛的体外研究。胰腺癌生物学中的一个重要问题是疾病中观察到的基因组异质性的原因和后果。然而，要将胰腺癌组织器官用作研究基因组变异的模型，我们需要首先了解器官内基因组异质性的程度及其在器官内的稳定性。在这里，我们使用单细胞全基因组测序来研究两个独立的胰腺癌组织器官系列的基因组异质性，以及它们在延长培养期间的基因组稳定性。在器官内观察到具有相似拷贝数剖面的克隆群体，并且这些克隆群体的比例随着延长培养期而改变，表明一些克隆群体具有生长优势。然而，在每个克隆群体内也观察到亚克隆基因组异质性，表明胰腺癌细胞本身的基因组不稳定性。此外，我们的转录组分析还揭示了拷贝数改变和基因表达调控之间的正相关关系，表明这些拷贝数变化的"基因剂量效应"可以转化为基因表达调控。 ©2022年作者。

The establishment of patient-derived pancreatic cancer organoid culture in recent years creates an exciting opportunity for researchers to perform a wide range of in vitro studies on a model that closely recapitulates the tumor. One of the outstanding question in pancreatic cancer biology is the causes and consequences of genomic heterogeneity observed in the disease. However, to use pancreatic cancer organoids as a model to study genomic variations, we need to first understand the degree of genomic heterogeneity and its stability within organoids. Here, we used single-cell whole-genome sequencing to investigate the genomic heterogeneity of two independent pancreatic cancer organoid lines, as well as their genomic stability with extended culture. Clonal populations with similar copy number profiles were observed within the organoids, and the proportion of these clones was shifted with extended culture, suggesting the growth advantage of some clones. However, sub-clonal genomic heterogeneity was also observed within each clonal population, indicating the genomic instability of the pancreatic cancer cells themselves. Furthermore, our transcriptomic analysis also revealed a positive correlation between copy number alterations and gene expression regulation, suggesting the "gene dosage" effect of these copy number alterations that translates to gene expression regulation.© 2022. The Author(s).