Polyclonal-to-monoclonal transition in colorectal precancerous evolution

• 成果类型: Article
• 署名作者: 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
• 署名单位: Chinese Academy of Sciences; Shenzhen Institute of Advanced Technology, CAS; Chinese Academy of Sciences; Shenzhen Institute of Advanced Technology, CAS; University of Macau; Sun Yat Sen University; Xiamen University; Xiamen University; University of Macau; Sun Yat Sen University; Sun Yat Sen University; Sun Yat Sen University; Hong Kong University of Science & Technology; Sun Yat Sen University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5111
• DOI: 10.1038/s41586-024-08133-1
• 发表日期: 2024-12-05
• 关键词: copy number; stem-cells; cancer; adenomas; FRAMEWORK; Mutation; patient; models; tumors

摘要

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.