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

Significance

Metastasis is a major cause of cancer mortality. However, the regulation of this complex process remains poorly understood. Due to low oxygen supply and enhanced sugar metabolism, cancer cells releases lactate to create an acidic environment. We show that a membrane receptor on macrophages called G protein-coupled receptor 132 (Gpr132) can sense and respond to this lactate signal from cancer cells. As a result, macrophages alter their functions, which, in turn, stimulates cancer metastasis to distant organs. Consequently, loss of Gpr132 in mice inhibits breast cancer metastasis; lower Gpr132 expression in patients with breast cancer correlates with better metastasis-free survival. These findings uncover knowledge and potentially novel treatment for cancer metastasis.

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.