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Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α–mediated tumor progression

Lookup NU author(s): Dr Arian Laurence


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© 2018 American Society for Clinical Investigation.All right reserved. Macrophages perform key functions in tissue homeostasis that are influenced by the local tissue environment. Within the tumor microenvironment, tumor-associated macrophages can be altered to acquire properties that enhance tumor growth. Here, we found that lactate, a metabolite found in high concentration within the anaerobic tumor environment, activated mTORC1 that subsequently suppressed TFEB-mediated expression of the macrophage-specific vacuolar ATPase subunit ATP6V0d2. Atp6v0d2–/– mice were more susceptible to tumor growth, with enhanced HIF-2α–mediated VEGF production in macrophages that display a more protumoral phenotype. We found that ATP6V0d2 targeted HIF-2α but not HIF-1α for lysosome-mediated degradation. Blockade of HIF-2α transcriptional activity reversed the susceptibility of Atp6v0d2–/– mice to tumor development. Furthermore, in a cohort of patients with lung adenocarcinoma, expression of ATP6V0d2 and HIF-2α was positively and negatively correlated with survival, respectively, suggesting a critical role of the macrophage lactate/ ATP6V0d2/HIF-2α axis in maintaining tumor growth in human patients. Together, our results highlight the ability of tumor cells to modify the function of tumor-infiltrating macrophages to optimize the microenvironment for tumor growth.

Publication metadata

Author(s): Liu N, Luo J, Kuang D, Xu S, Duan Y, Xia Y, Wei Z, Xie X, Yin B, Chen F, Luo S, Liu H, Wang J, Jiang K, Gong F, Tang Z-H, Cheng X, Li H, Li Z, Laurence A, Wang G, Yang X-P

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2019

Volume: 129

Issue: 2

Pages: 631-646

Print publication date: 01/02/2019

Online publication date: 07/01/2019

Acceptance date: 13/11/2018

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation


DOI: 10.1172/JCI123027

PubMed id: 30431439


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