Single-cell transcriptomics reveals the landscape of intra-tumoral heterogeneity and stemness-related subpopulations in liver cancer

Cancer Lett. 2019 Sep 10:459:176-185. doi: 10.1016/j.canlet.2019.06.002. Epub 2019 Jun 10.

Abstract

Hepatocellular carcinoma (HCC) is heterogeneous, rendering its current curative treatments ineffective. The emergence of single-cell genomics represents a powerful strategy in delineating the complex molecular landscapes of cancers. In this study, we demonstrated the feasibility and merit of using single-cell RNA sequencing to dissect the intra-tumoral heterogeneity and analyze the single-cell transcriptomic landscape to detect rare cell subpopulations of significance. Exploration of the inter-relationship among liver cancer stem cell markers showed two distinct major cell populations according to EPCAM expression, and the EPCAM+ cells had upregulated expression of multiple oncogenes. We also identified a CD24+/CD44+-enriched cell subpopulation within the EPCAM+ cells which had specific signature genes and might indicate a novel stemness-related cell subclone in HCC. Notably, knockdown of signature gene CTSE for CD24+/CD44+ cells significantly reduced self-renewal ability on HCC cells in vitro and the stemness-related role of CTSE was further confirmed by in vivo tumorigenicity assays in nude mice. In summary, single-cell genomics is a useful tool to delineate HCC intratumoral heterogeneity at better resolution. It can identify rare but important cell subpopulations, and may guide better precision medicine in the long run.

Keywords: Cancer stem cell; Cancer stemness; HCC; Single-cell sequencing; Tumor heterogeneity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD24 Antigen / metabolism
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Epithelial Cell Adhesion Molecule / biosynthesis
  • Epithelial Cell Adhesion Molecule / genetics
  • Genetic Heterogeneity
  • Heterografts
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hyaluronan Receptors / metabolism
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Mice
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Single-Cell Analysis
  • Transcriptome

Substances

  • CD24 Antigen
  • CD24 protein, human
  • CD44 protein, human
  • EPCAM protein, human
  • Epithelial Cell Adhesion Molecule
  • Hyaluronan Receptors