中国科学院深圳先进技术研究院胡政、中山大学贺雄雷等合作取得一项新成果。经过不懈努力，他们发现在大肠癌癌前病变组织中存在多克隆向单克隆的转变。2024年10月30日，国际学术期刊《自然》发表了这一成果。

据介绍，了解癌前病变的起源和演变，对于有效预防癌症恶性转化至关重要，但目前这一方面的知识仍然有限。

研究人员利用碱基编辑器介导的DNA条形码系统，在炎症或Apc基因缺失诱导的小鼠肠道肿瘤发生模型中，全面绘制了单细胞系统发生图。通过对正常、炎症和肿瘤性肠道组织的260922个单细胞高分辨率系统发生图进行定量分析，研究人员在每个病变组织中发现了并行克隆扩增的数十个独立细胞系。

通过批量全外显子组测序和单样本全基因组测序，研究人员还发现了人类散发性结直肠息肉的多克隆起源。基因组和临床数据支持多克隆向单克隆转变的模型，单克隆病变代表更晚期的阶段。

单细胞RNA测序显示，在早期多克隆病变中存在广泛的细胞间相互作用，但在单克隆转变过程中，细胞间相互作用显著减少。因此，该研究数据表明，结直肠癌前病变往往是由许多不同的细胞系构成，并揭示出它们在癌症形成早期阶段的合作性相互作用。这些发现为早期结直肠癌干预提供了机会。

附：英文原文

Title: Polyclonal-to-monoclonal transition in colorectal precancerous evolution

Author: Lu, Zhaolian, Mo, Shanlan, Xie, Duo, Zhai, Xiangwei, Deng, Shanjun, Zhou, Kantian, Wang, Kun, Kang, Xueling, Zhang, Hao, Tong, Juanzhen, Hou, Liangzhen, Hu, Huijuan, Li, Xuefei, Zhou, Da, Lee, Leo Tsz On, Liu, Li, Zhu, Yaxi, Yu, Jing, Lan, Ping, Wang, Jiguang, He, Zhen, He, Xionglei, Hu, Zheng

Issue&Volume: 2024-10-30

Abstract: Unravelling the origin and evolution of precancerous lesions is crucial for effectively preventing malignant transformation, yet our current knowledge remains limited1,2,3. Here we used a base editor-enabled DNA barcoding system4 to comprehensively map single-cell phylogenies in mouse models of intestinal tumorigenesis induced by inflammation or loss of the Apc gene. Through quantitative analysis of high-resolution phylogenies including 260,922 single cells from normal, inflamed and neoplastic intestinal tissues, we identified tens of independent cell lineages undergoing parallel clonal expansions within each lesion. We also found polyclonal origins of human sporadic colorectal polyps through bulk whole-exome sequencing and single-gland whole-genome sequencing. Genomic and clinical data support a model of polyclonal-to-monoclonal transition, with monoclonal lesions representing a more advanced stage. Single-cell RNA sequencing revealed extensive intercellular interactions in early polyclonal lesions, but there was significant loss of interactions during monoclonal transition. Therefore, our data suggest that colorectal precancer is often founded by many different lineages and highlight their cooperative interactions in the earliest stages of cancer formation. These findings provide insights into opportunities for earlier intervention in colorectal cancer.

DOI: 10.1038/s41586-024-08133-1

Source: https://www.nature.com/articles/s41586-024-08133-1