RRC ID 62611
Author Nishida J, Momoi Y, Miyakuni K, Tamura Y, Takahashi K, Koinuma D, Miyazono K, Ehata S.
Title Epigenetic remodelling shapes inflammatory renal cancer and neutrophil-dependent metastasis.
Journal Nat Cell Biol
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.
Volume 22(4)
Pages 465-475
Published 2020-4-1
DOI 10.1038/s41556-020-0491-2
PII 10.1038/s41556-020-0491-2
PMID 32203421
MeSH 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
IF 20.042
DNA material CSII-EF-RfA (RDB04387) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)
Human and Animal Cells OS-RC-2(RCB0735)