2. Academic Validation
  3. Epigenetic remodelling shapes inflammatory renal cancer and neutrophil-dependent metastasis

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.
Jun Nishida 1,  Yusaku Momoi 1,  Kosuke Miyakuni 1,  Yusuke Tamura 1,  Kei Takahashi 1,  Daizo Koinuma 1,  Kohei Miyazono 2,  Shogo Ehata 3 4 5
Affiliations

Affiliations

  • 1 Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 2 Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [email protected].
  • 3 Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [email protected].
  • 4 Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [email protected].
  • 5 Environmental Science Center, The University of Tokyo, Tokyo, Japan. [email protected].
PMID: 32203421 DOI: 10.1038/s41556-020-0491-2
Abstract

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.

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