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Proc Natl Acad Sci U S A. 2017 Jan 17;114(3):580-585. doi: 10.1073/pnas.1614035114. Epub 2017 Jan 3.

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

Author information

1
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
2
Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
3
Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
4
Clayton Foundation Laboratories of Peptide Biology and Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies, La Jolla, CA 92037.
5
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390; yihong.wan@utsouthwestern.edu.

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.

KEYWORDS:

Gpr132; breast cancer; lactate; macrophage; metastasis

PMID:
28049847
PMCID:
PMC5255630
DOI:
10.1073/pnas.1614035114
[Indexed for MEDLINE]
Free PMC Article

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