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

Nat Commun. 2021 Jul 2;12(1):4091. 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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / immunology*
  • Cell Cycle
  • Cell Line, Tumor
  • Chemokine CCL5 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Genetic Heterogeneity*
  • Humans
  • Immune Evasion*
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplastic Cells, Circulating / immunology*
  • Neoplastic Cells, Circulating / metabolism
  • Prognosis
  • RNA-Seq
  • Transcriptome
  • Tumor Microenvironment


  • Biomarkers, Tumor
  • Chemokine CCL5