Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis

Peiwen Chen, Hao Zuo, Hu Xiong, Matthew J. Kolar, Qian Chu, Alan Saghatelian, Daniel J. Siegwart, Yihong Wan

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor-macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor-macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment.

Original languageEnglish (US)
Pages (from-to)580-585
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number3
DOIs
StatePublished - Jan 17 2017

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G-Protein-Coupled Receptors
Lactic Acid
Macrophages
Breast Neoplasms
Neoplasm Metastasis
Neoplasms
Tumor Microenvironment
Cell Adhesion
Cell Movement
Lung Neoplasms
Communication
Phenotype
Therapeutics

Keywords

  • Breast cancer
  • Gpr132
  • Lactate
  • Macrophage
  • Metastasis

ASJC Scopus subject areas

  • General

Cite this

Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis. / Chen, Peiwen; Zuo, Hao; Xiong, Hu; Kolar, Matthew J.; Chu, Qian; Saghatelian, Alan; Siegwart, Daniel J.; Wan, Yihong.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 3, 17.01.2017, p. 580-585.

Research output: Contribution to journalArticle

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AU - Kolar, Matthew J.

AU - Chu, Qian

AU - Saghatelian, Alan

AU - Siegwart, Daniel J.

AU - Wan, Yihong

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AB - Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor-macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor-macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment.

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