title: Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast 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.
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Peiwen
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Hao
authors.initials: H
authors.lastname: Zuo
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390.|Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Hu
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Clayton Foundation Laboratories of Peptide Biology and Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Kolar
authors.affiliation: Clayton Foundation Laboratories of Peptide Biology and Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chu
authors.affiliation: Clayton Foundation Laboratories of Peptide Biology and Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390.|Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Siegwart
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390; yihong.wan@utsouthwestern.edu.|Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D011379:Prognosis; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D018797:Cell Cycle Proteins; C115270:G2A receptor; D043562:Receptors, G-Protein-Coupled; D019344:Lactic Acid
keywords: Gpr132; breast cancer; lactate; macrophage; metastasis