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

IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Signal Transduction and Targeted Therapy Pub Date : 2024-09-23 DOI:10.1038/s41392-024-01960-8
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
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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 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.

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单细胞外显子组测序揭示结肠癌转移中的多克隆播种和TRPS1突变
肝转移仍然是结肠癌患者死亡的主要原因。确定导致转移的特定驱动基因突变可提供可行的治疗靶点。为了探索转移瘤内的克隆进化和遗传异质性,我们对从一名 IV 期结肠癌患者的原发肿瘤、肝转移瘤和淋巴转移瘤中分离出的 150 个单细胞进行了单细胞外显子测序。肿瘤样本的基因图谱显示,淋巴转移灶和肝转移灶均源自原发肿瘤的同一区域。值得注意的是,肝转移灶直接来自原发肿瘤,绕过了淋巴结。对不同肿瘤内单个细胞对的测序数据进行的比较分析表明,肝转移灶和淋巴转移灶的遗传异质性也大于原发肿瘤。这一发现表明,肝转移瘤和淋巴转移瘤来自多克隆来源的循环肿瘤细胞(CTC)群,而不是来自原发肿瘤的单个细胞。单细胞转录组分析表明,较高的EMT评分和CNV评分与较多的多克隆转移有关。此外,肝转移瘤的单细胞中富含 TRPS1(转录抑制因子 GATA 结合 1)基因突变,即 TRPS1 R544Q。该基因突变通过 TRPS1R544Q/ZEB1 轴,明显增加了 CRC 在体外和体内的侵袭和迁移。在更多的结肠癌病例中检测到了更多的TRPS1突变,这些突变与晚期疾病和不良预后相关。这些结果揭示了多克隆播种和TRPS1突变是结肠癌肝转移发展的潜在驱动机制。
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来源期刊
Signal Transduction and Targeted Therapy
Signal Transduction and Targeted Therapy Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
44.50
自引率
1.50%
发文量
384
审稿时长
5 weeks
期刊介绍: Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy. Scope: The journal covers research on major human diseases, including, but not limited to: Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.
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