Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 3, Pages 580-585Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1614035114
Keywords
macrophage; breast cancer; metastasis; Gpr132; lactate
Categories
Funding
- Cancer Prevention Research Institute of Texas [RP130145, R1212]
- Department of Defense [W81XWH-13-1-0318]
- NIH [R01DK089113]
- Mary Kay Foundation [073.14]
- March of Dimes [6-FY13-137]
- Welch Foundation [I-1751, I-1855]
- UT Southwestern Endowed Scholar Startup Fund
- National Cancer Institute Cancer Center Support Grant [5P30CA142543]
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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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