Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma

• Published in: Nature communications Vol. 12; no. 1; pp. 1 - 14
• Main Authors: Sun, Yun-Fan, Wu, Liang, Liu, Shi-Ping, Jiang, Miao-Miao, Hu, Bo, Zhou, Kai-Qian, Guo, Wei, Xu, Yang, Zhong, Yu, Zhou, Xiao-Rui, Zhang, Ze-Fan, Liu, Geng, Liu, Sheng, Shi, Ying-Hong, Ji, Yuan, Du, Min, Li, Nan-Nan, Li, Gui-Bo, Zhao, Zhi-Kun, Huang, Xiao-Yun, Xu, Li-Qin, Yu, Qi-Chao, Peng, David H., Qiu, Shuang-Jian, Sun, Hui-Chuan, Dean, Michael, Wang, Xiang-Dong, Chung, Wen-Yuan, Dennison, Ashley R., Zhou, Jian, Hou, Yong, Fan, Jia, Yang, Xin-Rong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.07.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45/91; 631/67/1504/1610; 631/67/2329; 631/67/322; 631/67/580; Cell cycle; Cellular stress response; Chemokines; Circulatory system; Gene sequencing; Hepatic vein; Hepatocellular carcinoma; Heterogeneity; Humanities and Social Sciences; Immune evasion; Immunoregulation; Liver cancer; Lymphocytes; Lymphocytes T; Metastases; multidisciplinary; Portal vein; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Signaling; Spatial heterogeneity; Transcription; Transcriptomes; Transcriptomics; Tumor cells; Tumors; Veins; Veins & arteries
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24386-0

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC. Circulating tumour cells can be useful for monitoring disease progression but how they survive in the circulatory system is unclear. Here, the authors use single-cell sequencing of circulating tumour cells from multiple vascular sites in liver cancer patients and identify genes that may help the cells survive.