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

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 TRPS1<sup>R544Q</sup>/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.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2024-09-23
DOI
https://doi.org/10.1038/s41392-024-01960-8
Citations
18
Primary Topic
Cancer Genomics and Diagnostics
Type
article
Field-Weighted Citation Impact
5.13

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article

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

Jianming Ying, Zhen Huang, Jianmei Liu, Yalan Lu et al.
18 citations
Signal Transduction and Targeted Therapy
Cancer Genomics and Diagnostics
5.13
article

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

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

Abstract

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 TRPS1<sup>R544Q</sup>/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.

Signal Transduction and Targeted TherapyVol. 9(1)
Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking University (CN), National Cancer Center (US), Institute of Laboratory Animal Science (CN), Peking University Third Hospital (CN)
Guangdong Provincial Hospital of Traditional Chinese Medicine, National Natural Science Foundation of China, Chinese Academy of Medical Sciences, Sanming Project of Medicine in Shenzhen, National Key Research and Development Program of China
Openalex Percentile: Top 4%
Cancer Genomics and Diagnostics
5.13
DOIOpen Access PDFOpenAlex
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