Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer

Cancer Cell. 2019 Oct 14;36(4):418-430.e6. doi: 10.1016/j.ccell.2019.08.007. Epub 2019 Oct 3.

Abstract

Cellular diversity in tumors is a key factor for therapeutic failures and lethal outcomes of solid malignancies. Here, we determined the single-cell transcriptomic landscape of liver cancer biospecimens from 19 patients. We found varying degrees of heterogeneity in malignant cells within and between tumors and diverse landscapes of tumor microenvironment (TME). Strikingly, tumors with higher transcriptomic diversity were associated with patient's worse overall survival. We found a link between hypoxia-dependent vascular endothelial growth factor expression in tumor diversity and TME polarization. Moreover, T cells from higher heterogeneous tumors showed lower cytolytic activities. Consistent results were found using bulk genomic and transcriptomic profiles of 765 liver tumors. Our results offer insight into the diverse ecosystem of liver cancer and its impact on patient prognosis.

Keywords: VEGF; biodiversity; cholangiocarcinoma; hepatocellular carcinoma; liver cancer; microenvironmental reprogramming; single-cell; tumor ecosystem; tumor heterogeneity; tumor microenvironments.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use
  • Bile Duct Neoplasms / genetics*
  • Bile Duct Neoplasms / mortality
  • Bile Duct Neoplasms / pathology
  • Bile Duct Neoplasms / therapy
  • Bile Ducts, Intrahepatic / pathology
  • Bile Ducts, Intrahepatic / surgery
  • Biopsy
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / therapy
  • Cholangiocarcinoma / genetics*
  • Cholangiocarcinoma / mortality
  • Cholangiocarcinoma / pathology
  • Cholangiocarcinoma / therapy
  • DNA Copy Number Variations
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Variation
  • Hepatectomy
  • Humans
  • Liver / pathology
  • Liver / surgery
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Liver Neoplasms / therapy
  • Male
  • Middle Aged
  • Prognosis
  • Progression-Free Survival
  • RNA-Seq
  • Single-Cell Analysis
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Antineoplastic Agents, Immunological
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A