期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2102434118
关键词
GPCR; Olfr78; TAMs; OR51E2; lactate
资金
- National Research Foundation [2021R1A5A2021614, 2021R1A2C1009258]
- Bio & Medical Technology Development Program [2017M3A9G8083382, 2020M3A9D3038435]
- Korean Mouse Phenotype Center [2019M3A9D5A01102797]
- National Research Foundation of Korea [2021R1A5A2021614, 2019M3A9D5A01102797] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The study suggests that Olfr78 can sense tumor-derived lactate and, in conjunction with Gpr132, mediate the generation of protumoral M2-TAMs. The interaction between Olfr78 and lactate may serve as a therapeutic target for reducing tumor progression and metastasis.
Expression and function of odorant receptors (ORs), which account for more than 50% of G protein-coupled receptors, are being increasingly reported in nonolfactory sites. However, ORs that can be targeted by drugs to treat diseases remain poorly identified. Tumorderived lactate plays a crucial role in multiple signaling pathways leading to generation of tumor-associated macrophages (TAMs). In this study, we hypothesized that the macrophage OR Olfr78 functions as a lactate sensor and shapes the macrophage-tumor axis. Using Olfr78(+/+) and Olfr78(-/-) bone marrow-derived macrophages with or without exogenous Olfr78 expression, we demonstrated that Olfr78 sensed tumor-derived lactate, which was the main factor in tumor-conditioned media responsible for generation of protumoral M2-TAMs. Olfr78 functioned together with Gpr132 to mediate lactate-induced generation of protumoral M2-TAMs. In addition, syngeneic Olfr78-deficient mice exhibited reduced tumor progression and metastasis together with an increased anti- versus protumoral immune cell population. We propose that the Olfr78-lactate interaction is a therapeutic target to reduce and prevent tumor progression and metastasis.
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