Epigenetic remodelling shapes inflammatory renal cancer and neutrophil-dependent metastasis

Nat Cell Biol. 2020 Apr;22(4):465-475. doi: 10.1038/s41556-020-0491-2. Epub 2020 Mar 23.


Advanced clear cell renal cell carcinoma (ccRCC) frequently causes systemic inflammation. Recent studies have shown that cancer cells reshape the immune landscape by secreting cytokines or chemokines. This phenotype, called cancer-cell-intrinsic inflammation, triggers a metastatic cascade. Here, we identified the functional role and regulatory mechanism of inflammation driven by advanced ccRCC cells. The inflammatory nature of advanced ccRCC was recapitulated in a preclinical model of ccRCC. Amplification of cancer-cell-intrinsic inflammation during ccRCC progression triggered neutrophil-dependent lung metastasis. Massive expression of inflammation-related genes was transcriptionally activated by epigenetic remodelling through mechanisms such as DNA demethylation and super-enhancer formation. A bromodomain and extra-terminal motif inhibitor synchronously suppressed C-X-C-type chemokines in ccRCC cells and decreased neutrophil-dependent lung metastasis. Overall, our findings provide insight into the nature of inflammatory ccRCC, which triggers metastatic cascades, and suggest a potential therapeutic strategy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / mortality
  • Carcinoma, Renal Cell / secondary
  • Cell Line, Tumor
  • Chemokines, CXC / genetics
  • Chemokines, CXC / metabolism
  • Disease Progression
  • Epigenesis, Genetic*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Inflammation
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / mortality
  • Kidney Neoplasms / pathology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Lung Neoplasms / secondary
  • Lymphatic Metastasis
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Prognosis
  • Survival Analysis
  • Tumor Microenvironment / genetics
  • Xenograft Model Antitumor Assays


  • Chemokines, CXC
  • Neoplasm Proteins