Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor

Jing Yiing Wu, Tsai Wang Huang, Yi Ting Hsieh, Yi Fu Wang, Chia Chien Yen, Guan Lin Lee, Chang Ching Yeh, Yi Jen Peng, Ya Yi Kuo, Hsiu Ting Wen, Hui Chen Lin, Cheng Wen Hsiao, Kenneth K. Wu, Hsing Jien Kung, Yu Juei Hsu, Cheng Chin Kuo

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.

Original languageEnglish (US)
Pages (from-to)213-227.e5
JournalMolecular Cell
Volume77
Issue number2
DOIs
StatePublished - Jan 16 2020
Externally publishedYes

Keywords

  • cancer metastasis
  • metabolomics
  • PI3K-HIF-1α axis
  • succinate
  • SUCNR1
  • tumor microenvironment
  • tumor-associated macrophages

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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