Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma
Yun‐Fan Sun, Liang Wu, Shiping Liu, Miaomiao Jiang, Bo Hu, Kaiqian Zhou, Wei Guo, Yang Xu, Yu Zhong, Xiaorui Zhou, Zefan Zhang, Geng Liu, Sheng Liu, Ying–Hong Shi, Yuan Ji, Min Du, Nannan Li, Guibo Li, Zhikun Zhao, Xiaoyun Huang, Liqin Xu, Qichao Yu, David H. Peng, Shuang‐Jian Qiu, Hui‐Chuan Sun, Michael Dean, Xiangdong Wang, Wen Yuan Chung, Ashley R. Dennison, Jian Zhou, Yong Hou, Jia Fan, Xin‐Rong Yang
Abstract
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.