Polyclonal-to-monoclonal transition in colorectal precancerous evolution

Zhaolian Lu, Shanlan Mo, Duo Xie, Xiangwei Zhai, Shanjun Deng, Kantian Zhou, Kun Wang, Xueling Kang, Hao Zhang, Juanzhen Tong, Liangzhen Hou, Huijuan Hu, Xuefei Li, Da Zhou, Leo Tsz On Lee, Li Liu, Yaxi Zhu, Jing Yu, Ping Lan, Jiguang Wang, Zhen He (), Xionglei He () and Zheng Hu ()
Additional contact information
Zhaolian Lu: Chinese Academy of Sciences
Shanlan Mo: Chinese Academy of Sciences
Duo Xie: Chinese Academy of Sciences
Xiangwei Zhai: Sun Yat-Sen University
Shanjun Deng: Sun Yat-Sen University
Kantian Zhou: Chinese Academy of Sciences
Kun Wang: Chinese Academy of Sciences
Xueling Kang: Chinese Academy of Sciences
Hao Zhang: Chinese Academy of Sciences
Juanzhen Tong: Chinese Academy of Sciences
Liangzhen Hou: Chinese Academy of Sciences
Huijuan Hu: Chinese Academy of Sciences
Xuefei Li: Chinese Academy of Sciences
Da Zhou: Xiamen University
Leo Tsz On Lee: University of Macau, Taipa
Li Liu: Sun Yat-Sen University
Yaxi Zhu: Sun Yat-sen University
Jing Yu: Sun Yat-sen University
Ping Lan: Sun Yat-sen University
Jiguang Wang: Chinese Academy of Sciences
Zhen He: Sun Yat-sen University
Xionglei He: Sun Yat-Sen University
Zheng Hu: Chinese Academy of Sciences

Nature, 2024, vol. 636, issue 8041, 233-240

Abstract: Abstract Unravelling the origin and evolution of precancerous lesions is crucial for effectively preventing malignant transformation, yet our current knowledge remains limited1–3. 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.

Date: 2024
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DOI: 10.1038/s41586-024-08133-1

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