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.
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.
Signal Transduct Target Ther. 2024 Sep 23;9(1):247. doi: 10.1038/s41392-024-01960-8.
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/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.
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能提供可行的治疗靶点。为了探索转移灶中的克隆进化和遗传异质性，我们对一名 IV 期结肠癌患者的原发肿瘤、肝转移和淋巴结转移中分离的 150 个单细胞进行了单细胞外显子组测序。肿瘤样本的遗传图谱显示，淋巴结和肝转移均起源于原发肿瘤的同一区域。值得注意的是，肝转移直接来源于原发肿瘤，绕过了淋巴结。对不同肿瘤中单个细胞对的测序数据进行比较分析表明，肝转移和淋巴结转移的遗传异质性也大于原发肿瘤。这一发现表明，肝转移和淋巴结转移是由多克隆起源的循环肿瘤细胞（CTC）簇产生的，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 评分与更多的多克隆转移相关。此外，TRPS1（转录抑制因子 GATA 结合蛋白 1）基因中的突变 TRPS1 R544Q 在来自肝转移的单细胞中富集。该突变通过 TRPS1/ZEB1 轴显著增加了 CRC 的体外和体内侵袭和迁移能力。在其他结肠癌病例中也检测到了额外的 TRPS1 突变，与晚期疾病和预后不良相关。这些结果揭示了多克隆播种和 TRPS1 突变作为潜在的机制，推动了结肠癌肝转移的发展。
