Single-cell exome sequencing reveals polyclonal seeding and TRPS1 mutations in colon cancer metastasis  

作　　者：Jianqiang Cai Weilong Zhang Yalan Lu Wenjie Liu Haitao Zhou Mei Liu Xinyu Bi Jianmei Liu Jinghua Chen Yanjiang Yin Yiqiao Deng Zhiwen Luo Yi Yang Qichen Chen Xiao Chen Zheng Xu Yueyang Zhang Chaoling Wu Qizhao Long Chunyuan Huang Changjian Yan Yan Liu Lei Guo Weihua Li Pei Yuan Yucheng Jiao Wei Song Xiaobing Wang Zhen Huang Jianming Ying Hong Zhao 

机构地区：[1]Department of Hepatobiliary Surgery,State Key Laboratory of Molecular Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China [2]Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China [3]Department of Hematology,Lymphoma Research Center,Peking University Third Hospital,Beijing,China [4]Key Laboratory of Human Disease Comparative Medicine,Chinese Ministry of Health,Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases,Institute of Laboratory Animal Science,Chinese Academy of Medical Sciences and Comparative Medicine Center,Peking Union Medical College,Beijing,China [5]Department of Biochemistry and Molecular Biology,State Key Laboratory of Medical Molecular Biology,Institute of Basic Medical Sciences Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College,Beijing,China [6]Department of Colorectal Surgery,State Key Laboratory of Molecular Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China [7]State Key Laboratory of Molecular Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China [8]Department of Pathology,State Key Laboratory of Molecular Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第10期4637-4652,共16页信号转导与靶向治疗（英文）

基　　金：National Key Research and Development Program of China(2023YFC3403800);National Natural Science Foundation of China(81972311,82303782);special Funds of the National Natural Science Foundation of China(82141127);CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-12M-066);Non-profit Central Research Institution Fund of Chinese Academy of Medical Science(2019PT310026);Sanming Project of Medicine in Shenzhen(SZSM202011010).

摘　　要：Liver metastasis remains the primary cause of mortality in patients with colon cancer. Identifying specific driver gene mutations that contribute to metastasis may offer viable therapeutic targets. To explore clonal evolution and genetic heterogeneity within the metastasis, we conducted single-cell exome sequencing on 150 single cells isolated from the primary tumor, liver metastasis, and lymphatic metastasis from a stage IV colon cancer patient. The genetic landscape of the tumor samples revealed that both lymphatic and liver metastases originated from the same region of the primary tumor. Notably, the liver metastasis was derived directly from the primary tumor, bypassing the lymph nodes. Comparative analysis of the sequencing data for individual cell pairs within different tumors demonstrated that the genetic heterogeneity of both liver and lymphatic metastases was also greater than that of the primary tumor. This finding indicates that liver and lymphatic metastases arose from clusters of circulating tumor cell (CTC) of a polyclonal origin, rather than from a single cell from the primary tumor. Single-cell transcriptome analysis suggested that higher EMT score and CNV scores were associated with more polyclonal metastasis. Additionally, a mutation in the TRPS1 (Transcriptional repressor GATA binding 1) gene, TRPS1 R544Q, was enriched in the single cells from the liver metastasis. The mutation significantly increased CRC invasion and migration both in vitro and in vivo through the TRPS1R544Q/ZEB1 axis. Further TRPS1 mutations were detected in additional colon cancer cases, correlating with advanced-stage disease and inferior prognosis. These results reveal polyclonal seeding and TRPS1 mutation as potential mechanisms driving the development of liver metastases in colon cancer.

关 键 词：METASTASIS COLON cancer 

分 类 号：R735.35[医药卫生—肿瘤]